Annual
Reports 2022

Contents
02 Message from the Chairperson
03 Our Mission
04 Message from the Director: TMIMS2022
06 Special Team for COVID-19 Countermeasures: Message from Team Director
08 Organizational Chart • Our People at a Glance
09 Meet Our Scientists!
18

Our Goal

20 Research Activities
21

Department of Basic Medical Sciences

22

Genome Dynamics Project............................................................................................................. Hisao MASAI

23

Deafness Project..................................................................................................................................... Yoshiaki KIKKAWA

24

Calpain Project......................................................................................................................................... Yasuko ONO

25

Stem Cell Project.................................................................................................................................... Takahiko HARA

26

Protein Metabolism Project............................................................................................................ Yasushi SAEKI

27

Circadian Clock Project...................................................................................................................... Hikari YOSHITANE

28

Laboratory of Biomembrane......................................................................................................... Kohji KASAHARA

29 Department of Brain & Neurosciences
30 Dementia Research Project............................................................................................................ Masato HASEGAWA
31

Learning and Memory Project...................................................................................................... Minoru SAITOE

32

Neural Prosthesis Project................................................................................................................. Yukio NISHIMURA

33

Child Brain Project................................................................................................................................. Hiroshi SAKUMA

34

Stroke Renaissance Project............................................................................................................ Takashi SHICHITA

35

Developmental Neuroscience Project.................................................................................. Chiaki OHTAKA-MARUYAMA

37

Department of Psychiatry & Behavioral Sciences

38 Schizophrenia Research Project................................................................................................. Makoto ARAI39

Sleep Disorders Project..................................................................................................................... Makoto HONDA

40 Addictive Substance Project......................................................................................................... Kazutaka IKEDA
41

Frontier Research Laboratory....................................................................................................... Shinobu HIRAI

43

Department of Diseases & Infection

44

Viral Infection Control Project....................................................................................................... Fumihiko YASUI

45

Neurovirology Project......................................................................................................................... Satoshi KOIKE

46 Visual Research Project..................................................................................................................... Takayuki HARADA
47

Diabetic Neuropathy Project......................................................................................................... Kazunori SANGO

48 Regenerative Medicine Project................................................................................................... Yuichiro MIYAOKA
49 Cancer Immunology Project.......................................................................................................... Hidetaka TANNO
51

Research Centers

52

Research Center for Genome & Medical Sciences...................................................... Hideya KAWAJI

53	Research Center for Social Science & Medicine/
Unit for Mental Health Promotion.............................................................................................. Atsushi NISHIDA
54	Research Center for Social Science & Medicine/
Unit for Intractable Disease Nursing Care........................................................................... Yuki NAKAYAMA
55

Research Supports

56 Center for Basic Technology Research
57

Technology Licensing Office

58 Center for Medical Research Cooperation / Laboratory of Neuropathology
59 Public Relations and Other Activities
60 TMIMS Programs
62

Access Map

1   

Message from the Chairperson
Tokyo is the political, economic and cultural center of Japan.
Developing Tokyo into a more healthy welfare state will therefore
go a long way toward building a prosperous future for Japan. The
mission of the Tokyo Metropolitan Institute of Medical Science(TMIMS) is to promote research in the life and medical sciences
to improve the lives and health of the citizens of Tokyo. It is
well known that Japan has the most rapidly aging society in theworld. Tokyo, which reflects Japan itself, is undergoing a steadyincrease in cancers and infectious diseases, lifestyle-related
illnesses, neural and mental disorders, and various other healthproblems. Naturally, curing all of these diseases is a common
goal for all humankind, and considerable efforts have been madeat the national level. However, it is also essential for the Tokyo
Metropolitan Government to take the initiative in this endeavor.
Tokyo has numerous problems unique to megacities. For
instance, many people suffer from rare and intractable diseases
that researchers often overlook. TMIMS has been actively
working on these important problems, promptly and practicallyaddressing health-related issues with the aim of protecting thehealth of all Tokyo citizens.
From early 2020 to today, the highly contagious COVID-19
disease spread throughout the world causing unprecedented
damage at all levels of society. Combatting this disease isa top priority. At TMIMS, we swiftly set up a “Coronavirus
Countermeasures Special Team” three years ago and incooperation with the Tokyo Metropolitan Government, wehave been making every effort to develop effective strategies
to eliminate this disease. Particularly, epidemiological studies
such as monitoring of the resident population in the major
downtown areas of Tokyo have contributed greatly to the Tokyo
Metropolitan Government's countermeasures against COVID-19
disease, and we have also started our own highly original
vaccine development research against SARS-CoV-2. However,
unfortunately, the pandemic is still ongoing and TMIMS will needto continue fundamental research in order to develop effective
countermeasures to combat the disease in 2023.
Throughout history there has always been an ongoing struggle
between humans and infectious diseases. In the 21st century,
globalization and international human interactions have greatly
accelerated academic development and the elucidation anddissemination of new knowledge. However, globalization
has allowed the spread around the world. Thus, it is criticallyimportant for people in the modern world to have effective
strategies for preventing infectious diseases, minimizing theirspread, and developing effective cures without curtailinginternational interactions. This has generated a strong social
demand for medical advances and solutions. With this goal inmind, scientists at TMIMS will continue to dedicate themselves toadvancing basic and clinical research.
I am of the opinion that scientific research is a symbol of culture.
A society cannot be considered cultured if it has no interestand knowledge of science and research. Accordingly, TMIMS   2Chairperson

Keiji TANAKA
aims to be acclaimed both academically and culturally for theknowledge and wisdom of its excellent researchers. Our goal
is to become a symbol of the culture of Tokyo, the foremost
megalopolis in the world. Academic research is often roughly
divided into top-down, exit-oriented, applied research (ofimmediate use), and bottom-up, future-oriented basic research(seemingly not of immediate use). Balancing these two researchstrategies, TMIMS endeavors to operate in a flexible manner inorder to achieve additive and synergistic effects. Top-down andbottom-up research strategies are not incompatible, but canwork in a cooperative and harmonious manner. Throughout thehistory of science, we can find numerous examples of seemingly
useless research suddenly becoming useful, resulting in great
service to society.
Our medical researchers are energetically pursuing theirresearch to develop preventive medicine and new therapeutic
methods to protect citizens’ health. During this process, TMIMS
also takes on a role in educating young researchers who willcontinue to develop human knowledge and contribute to social
prosperity. All staff members of TMIMS are working on researchin the life sciences, ranging from fundamental to practical, using
cutting-edge technologies to achieve their goals.
We are working to make TMIMS the world’s premiere research
institute, and advancing and enriching its research power will
create an institute capable of providing wide-ranging services
to society. To this end, the entire staff of TMIMS strives to help
pursue incomparable fundamental research, and pass thebenefits of this research on to society. At the same time, we arecontinuing to recruit and educate talented people to increase ourmomentum. Thank you for your support, which is indispensablefor the further development of TMIMS.

Our Mission
The mission of TMIMS is to pursue research that will provide solutions for health-related
problems commonly observed in large urban areas and developed countries. We pursue
basic research to understand molecular and cellular mechanisms of biological pathways
and disease pathology, and collaborate with municipal hospitals and clinics to translate
basic research findings into technologies that can be used to predict, prevent, and treat
health problems. Toward this goal, we try to identify causes of unsolved diseases inorder to develop novel drugs and therapies. We study mental diseases to find effective
treatment, and investigate social factors that affect mental health of people in urban area.
We also contribute to improved care for those suffering from incurable diseases such as
ALS to better patients’ quality of life.

Public Health�
Prediction・Prevention・Diagnosis・Therapy・Care・Public relations�SocialMedicine�
Cohort studies・
Nursing care・Social support

Lifestyle diseases�

Infectious & other diseases�

CancerDementias
Neurodegeneratvie diseases
Diabetes

Pathogenesis・Vaccine
Brain stroke
Spinal cord injury

Schizophrenia
Tokyo Metro. Inst. Med. Science
Addiction(TMiMS)�
Sleep disorders and depression
Social environment

Mental diseases�

Parkinson’s disease
Muscular dystrophy
ALS

MedicalApplications�Collaboration
with hospitals
and industry

Genetic diseases

Genomics・Biochemistry・Mol Cell Biology・
Neurobiology・Genetics・Bioinformatics�

Basic Research�

3   Message fromthe Director: TMIMS 2022
respective fields. His paper on TDP-43, a causative factor forneurodegenerative diseases and dementia published in 2006,
was cited more than 2000 times and is in the top 0.1% of highimpact papers. We are very pleased that his long-term researchon the pathology and molecular basis of neurodegenerative
diseases has been recognized. Dr. Hasegawa continues to
uncover basic mechanisms of disease development andexpansion, and applies these findings to the development ofnovel drugs and therapies for treating people with dementias (seealso page 16).
We are currently in the third year of the 4th project term, and wehave started a “Frontier Research Laboratory” program in whichyoung researchers in the institute can conduct independent
research projects. Dr. Shinobu Hirai has been selected to head
the first Frontier Research Laboratory with a new research team,and we are eager to expand this program in the coming years.
The Coronavirus pandemic has prevented many activities andforced many events to be on-line. Scientific interactions withother institutes were limited, and we had not been able to invite
outside visitors. However, the situation improved much in 2022,
and many seminars and public lectures were conducted in a
hybrid manner, allowing both in-person and on-line interactions(see page 60).

Director

Hisao MASAIIn 2022, we witnessed the tragedy that an unjustified war brought
to people on this earth. Watching the tremendous loss of human
lives in Ukraine and Russia simply has made us speechless. As
scientists working to benefit humanity, we strongly oppose thissenseless war and hope this tragedy will end soon. On the brightside, the COVID pandemic finally seems to be abating somewhat.
After nearly three years, face-to-face meetings have finallyresumed, and many have started to attend meetings abroad.
Although life in Japan has not completely returned to normal,
we hope to soon return to a way of life where we are not living inconstant fear of infection.
TMIMS 2022
In September, we had very good news. Dr. Masato Hasegawa,the leader of the Dementia Research Project was selected asa 2022 Clarivate Citation Laureate. Clarivate Citation Laureatesare candidates considered likely to win the Nobel Prize in their   4

On December 6, 2022, we were able to host the 23rd TMIMSInternational Symposium, “New Frontiers in the Ubiquitin
Proteasome System” (organized by Dr. Yasushi Saeki of theProtein Metabolism Project). We invited 7 prominent scientists
from abroad who are leaders in the field. During the oneday meeting, these scientists as well as 6 invited speakers
from within Japan and 7 in-house speakers gave talks in theauditorium. There were heated questions and answers for every
talk, and the meeting was followed by a reception with muchfurther discussion. It had been three years since the last TMIMSinternational symposium, and we all thoroughly enjoyed face-toface interactions.
Two years ago, we created a program for inviting prominent
foreign scientists to visit and work at the institute for up to one
year. However, we had not been able to put this program into
action because of the pandemic. For the first time in 2022, we
decided to invite three foreign scientists through this program,and Dr. Gemma Knowles (King’s College London invited by Dr.
Atsushi Nishida) visited our institute last year. Next year morescientists will visit us through this program.
We have continued to develop pan-vaccines against SARSCoV-2 and conduct basic research to clarify mechanisms ofinfection and develop new drugs against infections. We havealso contributed to policy-making by the Tokyo Metropolitan
Government by providing social dynamics data.
Research achievements from our institute in 2022
We had numerous notable findings from this institute in 2022.
Dr. Taku Miyagawa in the Sleep Research Project discovered
an association between a genetic variant of the orexin geneand idiopathic hypersomnia. This genetic variation occurs at
the cleavage site on pre-pro orexin, and the variant showed asignificantly reduced cleavage rate. The uncleaved polypeptide
is less functional than the cleaved peptide, thus reducing thesignal transduction efficiency through the orexin receptor.
This is the first time that a significant risk factor for idiopathic
hypersomnia has been identified, and this work provides abreakthrough in clarifying the mechanism of this disease. The
finding was reported in npj Genomic Medicine (page 12). The
Circadian Clock project (led by Dr. Hikari Yoshitane) identified
a mechanism that stabilizes the circadian timekeeping system
in mammals through rhythmic transcription of Bmal1. These
results were published in Nature Communications and show
how circadian clock regulation may be maintained robustly.
Dr. Kosuke Tanegashima of the Stem cell project (led by Dr.
Takahiko Hara), in collaboration with Dr. Hitoshi Okamura’s
group at Kyoto University, found that expression of CXCL14,a chemokine, is regulated in a circadian manner. They further
found that CXCL14 regulates innate immunity and functions
to protect animals from bacterial skin infections. Overall, theirresults demonstrate that CXCL14-controlled innate immune
responses are more robust during circadian periods when
animals are asleep or inactive compared to when they are awake
and active. These findings were reported in the Proceedings of
the National Academy of Science of the United States of America(PNAS), and are described in further detail in an interview article(page 14). Dr. Tsuyoshi Takahashi and Yuichiro Miyaoka in the
Regenerative Medicine Project analyzed gene editing at a singlecell level. They found that gene editing either occurred in allalleles in a cell or in none. These findings revealed novel aspectsof gene editing and were reported in iScience. Other interesting
papers published this year are listed on our Home Page (https://www.igakuken.or.jp/topics/topics2022.html).
Science in 2022
The 2022 Nobel Prize in Physiology or Medicine was awarded
to Swedish paleogeneticist Svante Paabo for his discoveries
on the genomes of extinct hominins and in human evolution.
Dr. Paabo sequenced the genome of Neanderthals, an extinct
relative of Homo sapiens, and found that DNA sequences from
Neanderthals were more related to sequences from presentday humans originating from Europe or Asia than to sequencesfrom present-day humans from Africa. Dr. Paabo also discovereda previously unknown hominin, Denisova, from the Denisova
cave in southern Siberia, whose genome is distinct from those of
Neanderthals or Homo sapiens. He concluded that gene transfer
took place from these now-extinct hominins to Homo sapiens.
Homo sapiens are known to have first appeared in Africa around
300,000 years ago. They expanded out of Africa around 70,000
years ago, and coexisted with the Neanderthals in Eurasia fortens of thousands of years. During their millennia of coexistence,
Homo sapiens interbred with both Neanderthals and Denisovans,
and around 1% to 4% of the genome of present-day humans with
European or Asian origins is derived from Neanderthals. How we,humans, have evolved on this planet earth is a mind-provoking

question. With new technology, it has now become possible toexperimentally examine the evolutional path of human beings.
Science in Japan
We hear much these days about the declining strength ofscientific research in Japan. In 2000, Japan ranked 4th incountries with the most top 10% publications with 7.3%. In 2010,
Japan ranked 7th with 5.5%, and in 2020, 12th with 4%. During thisperiod, China moved from 13th to 3rd to first. In the last 20 years,
government research support increased by 20-fold in China(60 trillion yen) and doubled in the USA (70 trillion yen), while it
increased by only 20% in Japan (17 trillion yen). Besides problems
with funding, it appears that in Japan, being a scientist is not avery attractive carrier choice. Many aspiring young scientists havea hard time getting by in temporary positions and are forced togive up their careers as researchers. Young graduate students inJapan cannot see much of a bright future in pursuing academic
careers.
Japan has produced 27 Nobel laureates in the sciences and isranked No.7 in the world. We’ve had 22 recipients since 2000 andare one of the top 3 countries in this regard. This achievement ismainly due to the strong support by the Japanese government
for the basic sciences for last more than 40 years. The tree ofscience cannot grow without thick roots in the ground. The thickroots are the basic sciences that feed nutrients to the tree, whichthen produces ripe seeds. During hard times, the branches andleaves may be blown away, but the trunk will stay, as long as
the roots are solid, and the tree will be able to yield seeds in the
future. If the roots are fragile, the tree will not last, even though
the seeds look ripe. We need to protect and expand the roots.
Basic sciences need to be protected and grown even whenseeds seem to be in the distant future. The current trend inJapanese science policy is to look for seeds instead of nurturing
the basic sciences. Without watering the roots, the seeds will die,and the tree itself will wither away. I strongly urge the Japanese
government to increase support for all aspects of the basic
sciences. Only the basic sciences will uncover the mysteries ofnature that will bring us solutions that will revolutionize our lives.
Outlook for 2023
In 2023, we will continue to strive for creative discovery invarious biomedical fields including protein metabolism, genome
maintenance, brain functions and neurodegenerative diseases,
sleep disorders, circadian rhythms/aging, addiction, antibody
therapy, gene editing, mental diseases, viral infections and soforth. Our findings should lead to improved prediction, diagnoses,
and treatments for diseases.
With decreases in coronavirus severity and deaths, I hope ourway of life will be more normal this year. That said, we willcontinue our efforts to develop more versatile vaccines thatwill respond even to new variants of COVID-19 and to otherunpredictable emerging viruses/pathogens, and to establish
a common platform for vaccine development. We will also
continue to support the Tokyo Metropolitan Government by
providing information and medical technology to aid in policymaking.
I hope that the atrocities and tragedies of 2022 will be mitigatedin 2023 and we will be living on a more peaceful planet.

5   Special Team for
COVID-19
Countermeasures:
Message fromTeam Director

M.D., Ph.D.

Masanari ITOKAWA
Samurai-Scientist
The pandemic of severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) is worldwide public health emergency. We
have had plenty of tragic pandemic in history of the earth.
We are surprised at finding the depiction of three Cs, closed
spaces, crowded places and close-contact settings, in “Plutarchi
Vitae Parallelae” which is a famous Roman history book. Many
folklores and legendary rules contain right behaviors from apoint of view for prevention of infectious diseases. We, however,
have known pandemic as infectious phenomenon derived by
the small invisible living organism such as viruses since thebeginning of Bacteriology in 19th centuries. Tokugawa shogunate
had prohibited learning European science and philosophy tomaintain feudalism for over 200 years. Science and medicine
have been imported from European countries because the   6shogunate changed the prohibition policy since the mid 18th
centuries. A lot of samurai became "Samurai-Scientists" bylearning Dutch medicine. Their first lime-lighted fine performancewas emergency medical care for the patients of the cholera
pandemic at the end of 19th centuries.
The special team constructed of full TMIMS specs
TMIMS is the organization constructed by over 600 scientists.
We are confronting against SARS-CoV-2 by gathering all ourscientific activities, full capability of administrative office andsupporting division. We are demonstrating our strength as theMetropolitan Institute in order to protect the life and safety for
citizens of Tokyo by performing the largest hospital cooperation
as 7,000 beds in 14 metropolitan and public corporation hospitals.

Watching the antibody against COVID-19
Dr. Michinori Kohara and colleagues of the TMIMS COVID-19
team had screened randomly selected blood samples ofmore than 27,000 people for antibodies against SARS-CoV-2
collaborating with the 14 hospitals owned by the Tokyo
Metropolitan government since June 1, 2020 through the end of
March, 2021. Monitoring the IgG and IgM against COVID-19 levelsin the local general population helps access the infection spread.
Dr. Kohara found larger amount of asymptomatic population thanthat of PCR-detected in Tokyo(1).
Toward the lifelong immunity
Dr. Kohara has also developed a vaccine based on highly
attenuated recombinant vaccinia virus. The preclinical testing
showed not only enough amount but also prolonged duration of
antibody suggesting long-term protection against ever-evolving
SARS viruses.
We are also developing novel antivirals and investigating factors
associated with increase of severity of COVID-19. Dr. Kohji
Kasahara has found a clue for potential novel drugs targeting a
glycolipid molecule his group found to be important for SARSCoV-2 infection. Dr. Yasushi Saeki has been analyzing patient
proteomes to detect cellular changes derived from infection.

Social dynamics and COVID-19
Dr. Atsushi Nishida and colleagues estimated populations
between 10 PM and midnight in seven Tokyo metropolitan areas
by using mobile phone location data. Mobile phone trajectories
were used to distinguish and extract on-site dining from stay-atwork and stay-at-home behaviors. Dr. Nishida found an increasein the number of symptom onsets after 1 week from the increased
volume of the nighttime population(2).
We, TMIMS COVID-19 team, are confronting against SARS-CoV-2
to protect the people’s life and health in Tokyo by using scientificresearch and technologies as descendants of the SamuraiScientists.
References
1. Sanada T, Honda T, Yasui F, Yamaji K, Munakata T, Yamamoto
N, Kurano M, Matsumoto Y, Kono R, Toyama S, Kishi Y, Horibe
T, Kaneko Y, Kakegawa M, Fukui K, Kawamura T, Daming W,
Qian C, Xia F, He F, Yamasaki S, Nishida A, Harada T, Higa
M, Tokunaga Y, Takagi A, Itokawa M, Kodama T, Kohara M*
Serologic survey of IgG against SARS-CoV-2 among hospital
visitors without a history of SARS-CoV-2 infection in Tokyo,
2020-2021 J. Epidemiol 2(2):105-111. 2022
2. N akanishi M, Shibasaki R, Yamasaki S, Miyazawa S, Usami
S, Nishiura H, Nishida A. On-site Dining in Tokyo During the
COVID-19 Pandemic: Time Series Analysis Using Mobile Phone
Location Data JMIR Mhealth Uhealth 9(5)e27342, 2021 |The weekly monitoring conference of Tokyo Center for Infectious
Disease Control and Prevention (A). Drs. Kohara (B) and Nishida (C)are reporting their data.
[Image: From“ Tokyo Metropolitan Government
Official Video Channel (https://tokyodouga.jp/) ”]

7   Organizational Chart
Board Chairperson:

Keiji TANAKA
Vice-chairperson: Keiji GOTO

Director General:

Hisao MASAI

Vice Directors General: Masanari ITOKAWA
Minoru SAITOE

Field of Research(Department)

Basic Medical Sciences (Takahiko HARA)
Brain & Neurosciences (Masato HASEGAWA)
Psychiatry & Behavioral Sciences (Kazutaka IKEDA)
Diseases & Infection (Satoshi KOIKE)

Research Center for Genome & Medical Sciences(Hisao MASAI)

Research Center for Social Science & Medecine(Atsushi NISHIDA)

Center for Basic Technology Research(Minoru SAITOE)

Technology Licensing Office(Kazumasa AOKI)Center for Medical Research Coorperation(Takayuki HARADA)

Secretariat General Manager(Sanae SAKATA)

Our People at a Glance
152
69
157
137
141
33
689
   8

February 1, 2023

Meet ourscientists!

Meet Our Scientists!
Inflammation is a critical immune response to attacks from bacteria, viruses, and other harmful substances. It functions toeliminate these harmful substances and clear out dead and damaged tissue. However, inflammation also has deleterious
effects on the body. For example, neuroinflammation contributes to the severity of many neurodegenerative diseases.
Thus, it is crucial to understand the molecular and cellular pathways causing inflammation. One of the goals of the Visual
Research Project, led by Takayuki Harada, at TMIMS is to better understand diseases such as glaucoma or multiple
sclerosis (MS) in order to develop more effective treatments. Previously, members from this project, including Xiaoli
Guo, discovered that knocking out apoptosis signal-regulating kinase 1 (ASK1), a gene implicated in neuroinflammation,
decreases the severity of a mouse model of MS. More recently, Guo and her colleagues identified the cell types andcellular and molecular interactions necessary for ASK1’s role in inducing neuroinflammation in MS. This work, “ASK1
signaling regulates phase-specific glial interactions during neuroinflammation,” was published in the Proceeding of the
National Academy of Science, USA (Proc Natl Acad Sci U S A. 2022 Feb 8;119(6):e2103812119. doi: 10.1073/pnas.2103812119).
We spoke to Dr. Guo about her work and her interest in science.

XiaoliGuo

How did you become interested in science?
I was born in the countryside in China. We were very poor,so we had to be very self-sufficient. We grew our own
crops and raised farm animals such as chickens and pigs
for food. I think I naturally became interested in biology
because I was exposed to animals and living things fromsuch an early age.
Why did you decide to pursue research in Japan?
When I was a master’s student in China, I came to Japanas an exchange student between universities. I enjoyed
it so much that I applied for a scholarship from theJapanese government and came to Japan for my Ph.D. I
later pursued post-doctoral work in the United States, but
I missed my husband in Japan, so I returned here after
my post-doc and joined Dr. Harada’s lab at TMIMS, since I
enjoy working on visual systems and neurodegenerative
diseases.
Could you explain your latest publication on ASK1 andneuroinflammation?
In 2010, we published a paper on the role of ASK1 inexperimental autoimmune encephalomyelitis (EAE), amouse model for MS. MS is an inflammatory autoimmune
disease characterized by demyelination of neurons.
EAE is a classic model for MS that is generated byinjecting a myelin basic protein peptide into mice togenerate an autoimmune response to myelin. Similar
to MS, EAE induces demyelination of neurons, severe
neuroinflammation, and neuronal death. We found thatknocking out ASK1 decreases EAE symptoms, but wedidn’t know exactly why this happened. We didn’t know
the cell types where ASK1 was activated, and we didn’tknow the pathway through which ASK1 affects the severity   10

of EAE. ASK1 is also involved in other neurodegenerative
diseases including glaucoma, amyotrophic lateralsclerosis, Alzheimer’s disease, and Parkinson’s disease, so
understanding how ASK1 induces inflammation should be
important for developing treatments for many diseases.
In our current paper, we worked to understand the cells
and pathways that are activated by ASK1 to increase
disease symptoms. Various types of immune cells are
known to be involved in neuroinflammation, including
T-cells, dendritic cells, microglia, macrophages, andastrocytes. We made conditional knockouts of ASK1 ineach of these cell types to understand which cells needto express ASK1 to induce neuroinflammation. Altogether
we found that ASK1 is needed in microglia early during
EAE to start the inflammatory process, and then it’slater needed in astrocytes to maintain inflammation. To
start inflammation, many proinflammatory cytokine/
chemokine signaling genes need to be expressed, and
ASK1 in microglia is needed for this to occur. Activation of
microglia in turn, activates astrocytes which are needed
to maintain inflammation. We found that this interaction
between microglia and astrocytes also requires ASK1 inboth microglia and astrocytes. Without ASK1 in both cell
types, activation of astrocytes doesn’t occur. Altogether,
we identified different cell interactions and molecularinteractions through which ASK1 causes and maintains
neuroinflammation. We hope to use this information todevise future strategies for treating neurodegenerative
diseases.
What are your future plans?
We’re interested in developing novel treatments forglaucoma and MS. To do this, we’re pursuing threestrategies. First, we’re collaborating with a pharmaceuticalcompany to evaluate the effects of ASK1 inhibitor
treatments on MS and other diseases. Second, we’repursuing gene therapy approaches. In MS, myelin inoligodendrocytes is destroyed by autoimmune reactions.
Using gene therapy, we plan to increase amounts ofactivated TrkB in oligodendrocytes to see if this induces
remyelination. Third, we’re examining cell replacement
strategies using stem cells. I just came back from Kobe
Eye Center, where I learned how to make retinal ganglion
cells from stem cells. We plan on making retinal ganglion
cells and oligodendrocytes from stem cells to determine
whether addition of these cells may reduce disease
symptoms. MS is an extremely painful disease for bothpatients and their families. My hope is to contribute to
the development of new, good therapies to help thesepatients.
Interviewed by Jun Horiuchi

Schematic model of ASK1-mediated glial interaction during neuroinflammation.
Astrocytes and microglia activate each other in an ASK1-dependent manner. ASK1 signaling in microglia induces proinflammatory
astrocytes in the early stage of EAE and ASK1 signaling in astrocytes induces proinflammatory microglia and recruit macrophages
into the CNS in the late stage. ASK1-mediated activation of these glial cells causes sustained inflammation.

11   

Meet Our Scientists!
Sleep is an essential part of our lives, but even now, we only have a limited understanding of why sleep is so important.
What causes us to feel tired and fall asleep? Why do we feel so refreshed after waking? One way to understand sleep
better is to identify biological pathways regulating sleep. Traditionally geneticists study mutants defective in a biologicalprocess and compare them to normal animals to identify mutations in genes important for that biological process.
For example, narcolepsy type 1 is a neurological disease associated with defects in regulation of sleep-wake cycles.
Narcolepsy has been shown to be caused by a defect in production of orexin-A, a neuropeptide that excites various
brain nuclei to increase an animal’s wakefulness. However, in contrast to narcolepsy, the causes of a different sleep
disorder, idiopathic hypersomnia (IH), have been completely unknown. While narcolepsy patients tend to sleep for normal
amounts of time and wake up refreshed after sleeping, IH patients suffer intolerable sleepiness in the daytime and tend
to sleep much longer than normal. Taku Miyagawa, a staff scientist in the Sleep Disorders Project led by Makoto Honda,
is interested in understanding the causes of IH. Interestingly, he found that a rare missense variant in the cleavage siteof prepro-orexin is associated with IH. Thus, alterations in orexin signaling can be associated with two different sleep
disorders, narcolepsy and IH. This work was published in a paper, “A rare genetic variant in the cleavage site of preproorexin is associated with idiopathic hypersomnia,” (npj Genom.Med. 7, 29 (2022)). We spoke to him about his work.

Taku
Miyagawa

How did you become interested in science?
When I was a child, I liked history rather than science. But
in high school, most students picked physics or chemistry
as their science class, so the biology class I picked wasvery small and comfortable. My high school biology
teacher was fantastic and gave fascinating lectures
which piqued my interest in human genetics, medicine,and disease. I thought about a career in medicine, but
my mother, who was a nurse, discouraged me from   12

becoming a doctor, so instead, I pursued my interest in
genetic research.
Why did you start studying idiopathic hypersomnia (IH)?
I did my graduate work at Tokyo University, Departmentof Human Genetics, where I became interested in sleep
disorders. Sleep is a big mystery. We spend roughly onethird of our lives sleeping, but no one really knows why. I
performed genome-wide association studies to identify

narcolepsy-associated genes and I fortunately found one
gene. However, many groups are studying narcolepsy,
so I decided to change my target gene to IH, which few
people are studying. Although narcolepsy and IH are both
sleep disorders, they are different. Narcolepsy patientsactually sleep for normal amounts of time. So, they might
sleep for a total of about 7 hours per day and they wakeup refreshed. On the other hand, IH patients sleep much
more than normal, over 10 hours per day, but they’realways tired. So the questions we have for each disease
are different. For narcolepsy, we want to know whypatients suddenly fall asleep. For IH, we want to know
why patients have trouble sleeping even though they are
tired, and why sleep doesn’t cause patients to become
refreshed. In many respects, IH may be a much more
severe disease compared to narcolepsy.
Could you explain your 2022 Genomic Medicine paper?
In this paper, we found that orexin signaling is involved
in IH. Reductions in orexin signaling are well-known tocause narcolepsy; narcolepsy in dogs can be caused
by mutations in an orexin receptor, and narcolepsy inhumans is caused by the death of orexin-producing
cells. On the other hand, IH was thought to be caused
by a different mechanism because amounts of orexinin the cerebrospinal fluid of IH patients are relatively
normal, and because the two diseases have very different
symptoms. However, when we sequenced the orexin
and orexin receptor genes in IH patients and controls, wefound that the frequency of a rare missense variant in the
prepro-orexin gene was significantly higher in IH patients.
Mature orexin is produced by cleavage of a longer
prepro-orexin peptide, and we found that the cleavage

efficiency of the rare variant was lower than that of wildtype. Further, we found that activation of orexin receptors
by uncleaved prepro-orexin is decreased relative toactivation by mature orexin peptides. Overall, our results
demonstrate that at least some types of IH are associatedwith decreased orexin signaling.
Narcolepsy and IH have very different phenotypes. Why
do you think two very different diseases can result fromabnormalities in the same sleep pathway?
I think IH results from a partial reduction in orexin
signaling, while narcolepsy is caused by a completeor almost complete reduction. 100% reductions leadto narcolepsy, while lesser 50% reductions may be
associated with IH.
Do you think treating IH patients with orexin antagonists
could make them more like narcolepsy patients andresolve their tiredness?
That’s an interesting idea. I know that many
pharmaceutical companies are trying the opposite idea.
They are trying to produce orexin agonists that will
increase wakefulness.
How do you plan to continue your experiments in the
future?
In our previous paper, we looked for mutations andvariants in the orexin pathway. In the future, I’d like to lookfor completely novel mutations associated with IH using
genome-wide studies. From this, we should be able toidentify new pathways involved in sleep disorders.
Interviewed by Jun Horiuchi

Manhattan plot of a genome-wide association study of narcolepsy
13   Meet Our Scientists!
A lot of research has focused on antibodies and adaptive immunity, especially recently because of the coronavirus
pandemic. However, innate immune responses are also fascinating to study. They attack foreign invaders very quickly
although they have less specificity than antibodies. Recently, Kosuke Tanegashima, a staff scientist in the Stem Cell Project,
led by Takahiko Hara, identified a novel innate immunity mechanism that is regulated in a circadian manner. Immune
responses are greater during an animal’s subjective nighttime, when they are inactive, compared to their subjective
daytime, when they are active. His work was published in a paper, “Circadian protection against bacterial skin infection
by epidermal CXCL14-mediated innate immunity,” in the Proceeding of the National Academy of Science, USA (Proc Natl
Acad Sci U S A. 2022 Jun 21;119(25):e2116027119. doi: 10.1073/pnas.2116027119. Epub 2022 Jun 15). We spoke to him about
his interest in science, his research, and why he thinks it makes sense for some immune responses to be regulated in acircadian manner.

KosukeTanegashima
How did you first become interested in science?
I’ve been interested in science for as long as I canremember. My father used to grow plants and crops inour backyard, and when I was a child, I dug up theseplants to see their roots and flower bulbs. I wanted to see
how plants grow and develop. I think this initial interest
led me to pursue developmental biology using molecularbiology in college and postdoctal study. I later switchedto studying immunology since I thought molecularbiology that I learned could be applied to the medical
sciences. My current work on CXCL14 is particularlyinteresting to me since it has both medical implications
and involves elucidating novel mechanisms of activationof innate immune responses.

   14

Could you explain your recent work on innate immune
responses?
In our paper, we describe a novel innate immunity
mechanism that the epidermis uses to recognize
proliferation of Staphylococcus aureus. S aureus is abacterium that is normally found on the skin, but it canbecome pathogenic, causing infections and diseases
under a certain circumstances. We were studying achemokine called CXCL14. Chemokines are small,secreted proteins that cause inflammation by recruiting
immune cells to sites of infection or injury. However,even though I tried for a long time, I just couldn’t detectinflammatory responses when I added CXCL14 to cultured
cells. So, I thought that there may be some cofactor thatneeds to bind to CXCL14 to induce inflammation. SinceCXCL14 is a highly basic protein, I thought this cofactor
could be DNA, which is acidic. This idea turned out tobe correct, and we found that CXCL14 collaborates tocertain types of DNA, and this binding is needed to cause
inflammation and activate innate immune responses.
Interestingly, CXCL14 collaborates to S aureus DNA
but not E coli DNA. S aureus is found mainly on theskin, while E coli is found mainly in the gut, so CXCL14
binding specificity could have evolved to predominantly
recognize DNA from bacteria found on the skin.
How is this innate immune response regulated bycircadian rhythms?
Dr. Hitoshi Okamura’s group at Kyoto University
independently found that CXCL14 is expressed in the skinin a rhythmic, circadian fashion, but he didn’t know its
function. When we found out about each other’s work, we
decided to collaborate, and we discovered that CXCL14
induces inflammation and immune responses to S aureus
infections in a circadian manner. Mice are active during
the night and sleep during the day, while marmosets
are active during the day and sleep during the night.
In mice, CXCL14 is high during the day when they areinactive and low during the night when they are active.
Similarly, CXCL14 is high at night in diurnal marmosets
when they are asleep and low during the daytime when
they are active. We found that mice are more resistant toinfection by S aureus during the day when CXCL14 is highcompared to the nighttime when CXCL14 is low. Similarly,
we’d predict that diurnal animals including humanshould be more resistant to S aureus infections at nightcompared to daytime.

That’s fascinating! Why do you think immune responses
oscillate in a circadian manner?
We haven’t proven this, but this is what I think. We
have a limited amount of energy. When we are awake,
we participate in many activities that require a lot ofenergy, such as running or thinking or digesting. Immune
responses also require a lot of energy. When we areresting, we don’t have to use energy for activities suchas searching for food, eating, or running, so energy isavailable for immune responses. So, I think it’s reasonable
that during subjective nighttime, energy is directed toward
activities such as tissue repair and immune responses. For
really severe infections where you sleep during the day,maybe other mechanisms besides CXCL14 compensate
to increase immune responses during normally active
times.
What do you plan to do in the future?
I'm very interested in understanding how cells sense
DNA. DNA is a very common substance, and represents
the nature of living organisms. But we don’t know
how immune cells recognize and deal with DNA. It’s acompletely unknown field. So far, I’ve found that CXCL14
binds to S aureus DNA, and this CXCL14 DNA complex issomehow recognized by immune cells to induce immune
responses. However, we don’t know what receptor
recognizes this CXCL14-DNA complex. I’ve been looking
for this receptor by screening using expression cloning
and I’ve found several candidates that I’m excited about
studying.
Interviewed by Jun Horiuchi(A) A fluorescent image that shows CXCL14/DNA complexes incorporated into dendritic cells. (B) A schematic model of circadian clockmediated clearance of S. aureus by CXCL14. Expression of the Cxcl14 gene in epidermal keratinocytes is regulated by circadian rhythms.
When S. aureus invades skin keratinocytes, CXCL14 binds to bacterial DNA and transports it into dendritic cells (DCs) and macrophages toactivate innate immune defenses against the bacteria.
15   Meet Our Scientists!

MasatoHasegawa
This year, we were thrilled that Dr. Masato Hasegawa, thehead of the Dementia Research Project, was selected as a
Clarivate laureate. Clarivate laureates are chosen amongscientists who publish highly cited, high-impact papers
that strongly influence research in their respective fields,
and laureates are leading candidates for being awarded
the Nobel Prize. Dr. Hasegawa was chosen based on
his 2006 paper, “TDP-43 is a component of ubiquitinpositive tau-negative inclusions in frontotemporallobar degeneration and amyotrophic lateral sclerosis,”as well as his continuing work on the propagation ofneurodegerative diseases.
Neurodegenerative diseases can be separated into
several different classes. For example, tauopathies
including diseases such as Alzheimer’s disease, Pick’s
disease, corticobasal degeneration, and progressive
supranuclear palsy, are characterized by cytoplasmic
inclusions containing insoluble tau aggregates, while
synucleinopathies including diseases such as Parkinson’s
disease and dementia with Lewy bodies, are characterized
by inclusions containing α-synuclein aggregates. In
his landmark paper, Dr. Hasegawa and colleagues
determined that insoluble aggregates of a protein known   16

as TDP-43, compose a third class of neurodegenerative
disease which include frontotemporal lobar degeneration(FTLD) and amyotrophic lateral sclerosis (ALS). Thus, threemajor pathogenic proteins, tau, α-synuclein, and TDP-43
are involved in major neurodegenerative diseases.
Dr. Hasegawa has studied these three proteinsthroughout his career in order to determine the difference
between normal and abnormal versions, and elucidate
how abnormal versions aggregate, accumulate in thebrain, and spread to different regions of the brain. Early in
his career, he characterized alterations in phosphorylation
and ubiquitination in abnormal proteins and later helped
propose the influential “prion-like propagation” hypothesis
where abnormal proteins serve as seeds or templates
that convert normal proteins to aberrant forms which thenmultiply and spread throughout the brain. To support thishypothesis, Dr. Hasegawa showed in multiple studies,both in vitro and in vivo , that normal proteins on their own
very rarely convert to abnormal forms, while addition of atiny amount of abnormal protein results in a much fasterconversion to abnormal forms. The prion-like propagation
hypothesis is currently the predominant theory for
explaining disease progression. Dr. Hasegawa further

showed that abnormal proteins spread through neuronalconnections during disease progression.
What causes the differences between individual
neurodegenerative diseases? There are at least ten
distinct diseases associated with abnormal tau. Dr.
Hasegawa and colleagues determined that different
tauopathies were associated with different morphologicaltau filaments, and inoculating mice with different
filaments induced pathologies characteristic of different
diseases. He further collaborated in elucidating the crystal
structures of tau filaments from different tauopathies
and determined that different diseases had completely
distinct filamentous structures.

Dr. Hasegawa’s work has contributed much to ourunderstanding of the mechanisms that cause andpropagate neurodegenerative diseases. While we do not
yet have effective treatments to treat these diseases,
elucidating mechanisms of disease progression is thefirst step in this process, and through his work and thatof other scientists, we can hope for the development ofeffective treatments in the near future.
(Written by Jun Horiuchi)17   Ou r Go a l   18Our goal is to be a leading and role model institute for the life/medical
science by conducting cutting-edge basic, clinical and social medical
researches, that will help prediction, prevention, diagnosis, and treatmentof various diseases and improve the care of patients, leading to longer
healthy life.

19   

Research
Activities

Pluripotent Human iPS cells (upper) and organoid derived
from differentiated iPS cells (lower)

Basic
MedicalSciences

PROJECT / Basic Medical Sciences

Project Leader

Hisao MASAI

Hisao Masai, the director-generalof the institute since 2018, has led
the Genome Dynamics Projectsince 2009. After graduating fromthe University of Tokyo in 1981,
he worked on mechanisms of
DNA replication as a graduate
student under the supervisionof Dr. Ken-ichi Arai at DNAX
Research Institute in Palo Alto,
California, USA, and received his
Ph.D. in 1987 from the Universityof Tokyo, Graduate School of
Science. He has spent his career
studying how genetic informationi s d u pl ic a te d a nd inhe r ite d ,and what happens when theseprocesses fail. His current
interests include understanding
the enviroment-adaptive modeof DNA replication, how various
stresses arrest DNA replication
causes cancer, how replication iscoordinated with developmental
processes, and how unusual
nucleic acid structures andtheir interactions with specificproteins and membranes shapechromosomes, copy and read
genetic information, and how
failures of these processes cause
detrimental diseases.

GenomeDynamics
Laboratory HP: https://www.igakuken.or.jp/genome/

Staff
Senior Researcher
Hiroyuki SASANUMA
Researchers
Zhiying YOU
Taku TANAKA
Yutaka KANOH
Tomohiro IGUCHI
Yoichi TAJIMA
Sayuri ITO
Chi-Chun YANG

Research Assistants
Naoko KAKUSHO
Rino FUKATSU
Akiko MINAGAWA
Students
Karin HORI
Tomoko SAGI
Hao-Wen HSIAO
Trinh Thi To NGO
Maho SASHIDA

Zheng WENXIN
Bayrak MELIH
Ayaka ONUKI
Kosuke YAMAZAKI
Kanna HOTTA
Tatsuki FUKUSHIMA
Keisuke KATSUKI

Research Summary
Our goal is to understand the molecular mechanisms
responsible for faithful inheritance of genetic materials andstable maintenance of the genome. In particular, we focus on
elucidating regulatory mechanisms for DNA replication in E.
coli, fission yeast, and mammalian cells. Understanding how
chromosomes are replicated and inherited will allow us todetermine how defects in these processes cause diseases, suchas cancers, or lead to cellular senescence. From our studies, weare aiming to identify novel target proteins for cancer treatments
or amelioration of age-associate phenotypes. Specific questions
we are addressing are :1) How is the timing and location of DNA replication determined,
and how are these coordinated with other chromosomal
processes?
2) How do G-quadruplex structures regulate DNA regulation andchromosome architecture?
3) H ow do various biological stresses induce replication
checkpoint and how does it affect genome stability andpotentially cause cancer?
4) What are the roles of replication and checkpoint factors indevelopmental processes?

5) H ow have replication systems evolved and diversified in
response to changing environments?
6) H ow can we develop effective cancer therapies targeting
replication/ checkpoint factors?

A model for chromatin compartmentalization generated by Rif1 near nuclear periphery.
Rif1 protein binds to G4 structures in chromatin and promotes chromatin loop
formation through oligomerization. Rif1 also binds to nuclear membranes either directlyor through lipid modification, tethering chromatin fibers to the nuclear periphery. It canalso induce compartmentalization through liquid-liquid phase separation to generate

Selected Publications

confined, but dynamic and interactive chromatin compartments.

Kanoh et al . (2023) “Aberrant association of chromatin with nuclear periphry induced by

Kobayashi S, et al. (2019) “Both a unique motif at the C terminus and N-terminal HEAT

Rif1 leads to mitotic defect” Life Science Alliance 6(4): e202201603.

repeat contribute to G4 binding and origin regulation by Rif1 protein.” Mol Cell. Biol. 39(4):Yang and Masai (2023) “Claspin is required for growth recovery from serum starvation

You Z and Masai H (2017) “Potent DNA strand annealing activity associated with mouse

43(1): 1-21.

Mcm2~7 heterohexamer complex.” Nucleic Acids Res. 45: 6495-6506.

Yoshizawa-Sugata, et al. (2021) “Loss of full-length DNA replication regulator Rif1 inYang C-C, et al. (2016) “Claspin recruits Cdc7 kinase for initiation of DNA replication in

two-cell embryos is associated with zygotic transcriptional activation.” J Biol Chem, 297:

human cells.” Nature Communications 7: 12135.

101367.
Yang C-C, et al. (2019) “Cdc7 activates replication checkpoint by phosphorylating the
Chk1 binding domain of Claspin in human cells.” E-life, 8. pii: e50796   22e00364-18

through regulating the PI3K-PDK1-mTOR pathway in mammalian cells.” Mol. Cell. Biol.

Kanoh Y, et al. (2015) “Rif1 binds to G-quadruplexes and suppresses replication over long
distances.” Nature Struct. Mol. Biol. 22: 889-897.

Basic Medical Sciences / PROJECT

Project Leader

Yoshiaki KIKKAWA

Yoshiaki Kikkawa has beenleading the Deafness Projectsince 2020. Dr. Kikkawa
completed his Ph.D. on animal
genetics and evolution in 1998
from the Tokyo University ofAgriculture. He then worked inmouse genetics and genomics
under the supervision of Dr.
Hiromichi Yonekawa at TMIMS
where he identified key genes
involved in several diseases by
positional cloning. In particular, hefocused on using mouse models
to elucidate the molecularbasis for genetic deafness, andidentified Sans, one of the few
genes identified to date that areassociated with human deafness.
Subsequently he conducted
research on protein-protein
interactions associated with
deafness with Prof. Steve Brown
at the MRC, Harwell, UK, where
he discovered protein complexes
associated with stereocilia
elongation in hair cells in the
inner ear.

Deafness
Laboratory HP: https://www.igakuken.or.jp/mammal/english/index.html

Staff
Researchers
Shumpei YASUDA
Yuta SEKI

Research Assistants
Ai TAKAHASHI
Ting MAO
Ornjira PRAKHONGCHEEP

Students
Xuehan HOU

Research Summary
Hearing loss is a very common sensory disorder that severely
affects human quality of life. In order to develop effective
therapeutic strategies for deafness, it is critical to understand themechanisms regulating its onset. Our aim is to discover novel
genes associated with deafness. In particular, we are focusedon identifying genes responsible for age-related hearing loss
(ARHL). While genes responsible for congenital hearing loss havebeen identified, genes associated with ARHL, which affects a far
greater number of people, have not.
Many types of hearing loss are associated with loss of outer haircells (OHCs), which are responsible for the amplification of sound.
Thus, we study the development and maintenance of OHCs.
OHCs form a characteristic V-shaped stereocilia architecture.
However, the genetic and molecular mechanisms involved in
OHC development and death are poorly understood. To better
understand OHCs and ARHL, we are:1) Identifying genes causing and modifying ARHL in mousemodels using forward genetics approaches.
2) Functionally analyzing proteins involved in the developmentof the OHC V-shaped stereocilia architecture.

3) Investigating the molecular mechanisms involved in OHC
deaths using an OHC-specific depletion system.

The V-shaped stereocilia architecture of

OHC-specific expression of oncomodulin.

OHCs in 1-month-old mice. Stereocilia

Ocomodulin signals (red) werebundles are arranged in rows (blue,

specifically labeled in the nuclei of OHCs.

green, and magenta) of increasing

Green and blue signals indicate phalloidin

height and form a staircase-shaped

and DAPI staining.

configuration.

Selected Publications
Yasuda SP et al. (2022)“Two loci contribute to age-related hearing loss resistance in the

Seki Y, et al. (2017) “A novel splice site mutation of myosin VI in mice leads toJapanese wild-derived inbred MSM/Ms mice” Biomedicines 10: 2221

stereociliary fusion caused by disruption of actin networks in the apical region of inner

Seki et al. (2021) “Myosin VI haploinsufficiency reduced hearing ability in mice.”
Neuroscience. 478:100-111.
Yasuda SP et al. (2020) “c.753A>G genome editing of a Cdh23ahl allele delays age-related
hearing loss and degeneration of cochlear hair cells in C57BL/6J mice.” Hear. Res. 389:
107926.
Matsuoka K et al. (2019) “OHC-TRECK: A novel system using a mouse model forinvestigation of the molecular mechanisms associated with outer hair cell death in theear hair cells.” PLoS One 12, e0183477.
Miyasaka Y, et al. (2016) “Heterozygous mutation of Ush1g/Sans in mice causes earlyonset progressive hearing loss, which is recovered by reconstituting the strain-specificmutation in Cdh23.” Hum. Mol. Genet. 25: 2045-2059.
Kikkawa Y and Miyasaka Y. (2016) “Genetic modifiers of hearing loss in mice: The caseof phenotypic modification in homozygous Cdh23ahl age-related hearing loss.” Monogr.
Hum. Genet. 20: 97–109.

inner ear.” Sci. Rep. 9:5285.

23   

PROJECT / Basic Medical Sciences

CalpainLaboratory HP: https://www.igakuken.or.jp/calpain/indexEnglish.html

Project Leader

Yasuko ONO

Yasuko Ono has been the leaderof the Calpain Project since
2018. As a graduate student she
studied the roles of calpains, afamily of intracellular cysteine
proteases, in muscle functions,and received her Ph.D in 1999
from the University of Tokyo,
Graduate School of Science.
She then studied mechanismsof sarcomere assembly as
a postdoctoral fellow at the
University of Arizona. Her current
research includes studying thephysiological impact of calpainmediated proteolysis on cellularfunctions and understanding
mechanisms of calpain
regulation.

Staff
Researchers
Shoji HATA
Atsushi IRIE
Chihiro HISATSUNE
Fumiko SHINKAI-OUCHIAya NOGUCHI

Research Assistants
Naoko DOI

Research SummaryProteins are chains of amino acids, and their functions change
when they are cut or partially cut. Calpains are proteolytic
enzymes that perform such cuts or limited proteolytic processing

in cooperation with calcium. Humans have 15 calpain species.
Defects of these species cause various deficiencies, such as
muscular dystrophy, stomach ulcers, and embryonic lethality.

In this project, we aim to understand the biology of calpains, and translate thisknowledge into improvements in health.

Selected Publications
Shinkai-Ouchi F, et al. (2020) “Calpain-2 participates in the process of calpain-1
inactivation.” Biosci. Rep., 40: BSR20200552.

Shinkai-Ouchi F, et al. (2016) “Predictions of cleavability of calpain proteolysis by

Hata S, et al. (2020) “A muscle-specific calpain, CAPN3, forms a homotrimer.” Biochim.

quantitative structure-activity relationship analysis using newly determined cleavage

Biophys. Acta, Proteins Proteomics, 7: 140411.

sites and catalytic efficiencies of an oligopeptide array.” Mol. Cell. Proteomics, 15: 1262-

Hata S, et al. (2016) “A gastrointestinal calpain complex, G-calpain, is a heterodimer1280.

of Capn8 and Capn9 calpain isoforms, which play catalytic and regulatory roles,

Ono Y, et al. (2014) “The N- and C-terminal autolytic fragments of CAPN3/p94/calpain-3

respectively.” J. Biol. Chem., 291: 27313-27322.

restore proteolytic activity by intermolecular complementation.” Proc. Natl. Acad. Sci.

Ono Y, et al. (2016) “Calpain research for drug discovery: challenges and potential.”   24

Nature Reviews: Drug Discovery,15: 854-876.

USA, 111: E5527-5536.

Basic Medical Sciences / PROJECT

Project Leader

Takahiko HARA

Takahiko Hara, the department
chief of the Institute since Aprilof 2018, has been the leader of
the Stem Cell Project since 2005.
After receiving Ph.D from the
Graduate School of Science, Univ.
of Tokyo in 1990, he conducted
researches at DNAX ResearchInstitute in Palo Alto, California,
USA, as a postdoctoral fellow
under the supervision of Dr.
Atsushi Miyajima. He molecularlycloned a cDNA encoding mouse
IL-3 receptor alpha subunit. Next,
he developed ex vivo culture
system of hematopoietic stem
cells (HSCs) in the aorta-gonadmesonephros region of mouseembryo. Since then, molecularmechanism of HSC development
has been his major researchinterest. In the mean while, hestarted to investigated regulatorsof spermatogonial stem cells
and muscle regeneration factors.
Subsequently, he focused on a
RNA helicase DDX1 and a CXCtype chemokine CXCL14, as they
are involved in tumorigenesis
and anti-tumor immunity,
respectively.

Stem Cell
Laboratory HP: https://www.igakuken.or.jp/english/project/detail/stem-cell.html

Staff
Researchers
Kenji KITAJIMA
Kosuke TANEGASHIMA
Teruhiko SUZUKI
Masatoshi MURAOKA
Research Assistants
Tsuruyo TANIGUCHI

Students
Satoko TAKAGI
Shota HOYANO
Risa SAITO
Shiho SASAKI
Minako SHINGAI
Fumiya SEKI
Hikaru ANDO
Riku TAKAHASHI

Research Summary
Dr. Yamanaka’s inducible pluripotent stem cell (iPSC) technology
has opened a new avenue to overcome incurable diseases bycell transplantation. In 2011, we discovered that overexpressionof Lhx2 (transcription factor) in hemogenic mesodermal cells
resulted in ex vivo expansion of transplantable HSCs from mouseembryonic stem cells (ESCs) and iPSCs. Since then, we havebeen making efforts for applying this method to human iPSCs.
We believe that comparison of the in vitro differentiation capacityof hematopoietic cells between mouse and human iPSCs
will uncover novel and fundamental aspects of human HSC
development.
We discovered that CXCL14 is one of the causative factors
for obesity-associated diabetes. In contrast, CXCL14 is known
to possess tumor-suppressive activity against lung and oral
carcinomas. In 2017, we found that CXCL14 carries CpG DNA
into dendritic cells. This causes activation of the TLR9 signaling
pathway, which is effective in immune-suppression of cancers.
We are vigorously investigating physiological roles of CXCL14
and its action mechanisms. CXCL14 is a promising tool fordeveloping novel anti-cancer and anti-diabetes drugs.

The presence of cancer stem cells has been proposed in various
types of human cancer. Presumably, both tissue and cancer
stem cells commonly express critical transcriptional regulatorsand signal transducers. We have identified DDX1 (RNA helicase)and PTPN23 (tyrosine phosphatase) as essential molecules forthe onset of testicular tumors. In 2020, we discovered that DDX1
is essential for ribosome RNA metabolism in ESCs and cancer
cells. In the absence of DDX1, these cells stop proliferation andundergo apoptosis by p53 activation (Figure).

Conditional knockout system of ES cells uncovered a novel role of DDX1 in ribosome
RNA processing which is linked to p53-mediated cell growth control.

Selected Publications
Tsujihana, K., Tanegashima, K. et al. (2022)”Circadian protection against bacterial skin

Nakajima M, et al. (2019) “In vitro differentiation of mouse T cell-derived hybrid cells

infection by epidermal CXCL14-mediated innate immunity.” Proc. Natl. Acad. Sci. U.S.A.,

obtained through cell fusion with embryonic stem cells.” Biochem. Biophys. Res.

119: e2116027119, 2022.

Commun. 513: 701-707.

Iwase, R. et al. (2021)“Identification of functional domains of CXCL14 involved in high-Kitajima K, et al. (2018) "Domain-specific biological functions of the transcription factor

affinity binding and intracellular transport of CpG DNA.” J. Immunol., 207: 459.

Gata2 on hematopoietic differentiation of mouse embryonic stem cells." Genes Cells 23:

Suzuki, T. et al. (2021) “A novel all-in-one conditional knockout system uncovered anessential role of DDX1 in ribosomal RNA processing.” Nucl. Acid Res., 49: e40.
Sato K, et al. (2020) “Nitric oxide and a conditioned medium affect the hematopoietic
development in a microfluidic mouse embryonic stem cell/OP9 co-cultivation system.”

753-766.
Tanegashima K, et al. (2017) “CXCL14 acts as a specific carrier of CpG DNA into dendritic
cells and activates Toll-like receptor 9-mediated adaptive immunity.” EBioMed. 24: 247256.

Micromachines, 11: 305.

25   

PROJECT / Basic Medical Sciences

Project Leader

Yasushi SAEKI

Yasushi Saeki has been
the leader of the Protein
Metabolism Project since 2019.
He received his Ph.D. in 2003
from the Graduate Schoolof Pharmaceutical Sciences,
Hokkaido University. After
working as a JSPS research
fellow at the Univ. of Tokyo,
he joined the laboratory of Dr.
Keiji Tanaka in 2007. He has
been studying the ubiquitinproteasome system and has
identified the last proteasome
subunit, multiple proteasomespecific chaperones, and key
regulators for proteasomal
degradation. He has also
developed methods for analyzingproteasome activity and ubiquitin
chain topology. Since 2018, he
has also led the Grantin-Aid
Scientific Research on Innovative
Area ‘New frontier for ubiquitin
biology driven by chemotechnologies’ and works topromote collaborative researchon ubiquitin in Japan.

Protein
Metabolism
Laboratory HP: https://www.igakuken.or.jp/pro-meta/eng/

Staff
Researchers
Yukiko YOSHIDA
Akinori ENDO
Hikaru TSUCHIYA
Takuya TOMITA
Daiki KINOSHITA
Emeritus Researcher
Hiromichi YONEKAWA
Visiting Scientists
Fumiaki OHTAKE
Sayaka YASUDA
Yosuke DEMIZU
Gosuke HAYASHI

Supervisor
Students
Keiji TANAKA
Kota NAKADAI
Research Assistants
Liu DONGQI
Naoko ARAI
Takuro SUGIMOTO
Sayaka ONO
Chikage TAKAHASHI
Chikara ANDO
Meari YOSHIDAOKADAHarumi SETO
Kyoko UEDA

Research Summary
The ubiquitin-proteasome system (UPS) is a crucial protein
degradation system that affects almost all cellular functions
in eukaryotic cells. Since protein homeostasis is essential tohuman health, malfunctions of the UPS cause various diseases
including cancers, inflammation, and neurodegeneration. Thus,
UPS regulators are attracting attention as drug discovery targets.
However, there is still much unknown about the UPS. Our goal isto elucidate the fundamental mechanisms of ubiquitin signaling
and proteasomal degradation and to integrate this information
into pathophysiology to develop therapeutic strategies for UPSrelated diseases. To this end, we are currently focusing on thefollowing research projects.
1) D eciphering the ubiquitin code: The structural diversity ofubiquitin chains with distinct topologies, called the ‘ubiquitin
code,’ regulates the diverse functions of ubiquitin. We haveshown that the branching and length of ubiquitin chainsprovide additional specificity to this code (Nat Commun 2018,
Mol Cell 2021). To further investigate the ubiquitin code, weare developing methods to analyze the high-order structure ofubiquitin chains using advanced mass spectrometry.
2) D ecoding mechanisms for proteasomal degradation: We
have identified the p97-UFD1-NPL4 complex and RAD23
family as ubiquitin decoders that direct substrates to theproteasome (Mol Cell 2017, Nat Commun 2019). Currently weare investigating the substrate selectivity of these ubiquitin
decoders using advanced proteomics and by developing
chemical tools to manipulate proteasomal degradation.
3) B iological significance of proteasome phase separation:
Recently, we found the ubiquitin-dependent liquidliquid phase separation (LLPS) of the proteasome under
hyperosmotic stress (Nature 2020). This compartmentalization
appears to be advantageous for the rapid removal ofstress-damaged proteins, and we are further investigating
proteasome phase separation under various stress conditions.
4) G eneration of proteasome mutant mice: Recently, genemutations in the proteasome have been identified in patientswith autism and immune disorders. To understand thepathophysiological mechanism of "proteasomopathy", wegenerated proteasome mutant mice and are analyzing theirphenotypes.

Selected Publications
Kaiho-Soma A, et al. (2021) "TRIP12 promotes small molecule-induced degradation

Tsuchiya H, et al. (2018) “Ub-ProT reveals global length and composition of protein

through K29/K48 branched ubiquitin chains." Mol. Cell 81, 1411-1424.

ubiquitylation in cells.” Nat. Commun. 9, 524.

Yasuda S, Tsuchiya H, Kaiho Ai, et al. (2020) “Stress- and ubiquitylation-dependent

Ohtake F, et al. (2018) “K63 ubiquitylation triggers proteasomal degradation by seeding

phase separation of the proteasome.” Nature 578, 296-300.

branched chains.” Proc. Natl. Acad. Sci. USA. 115, E1401-E1408.

Sato Y, Tsuchiya H, et al. (2019) “Structural insights into ubiquitin recognition and Ufd1

Tsuchiya H, et al. (2017) “In vivo ubiquitin linkage-type analysis reveals that the Cdc48-

interaction of Npl4.” Nat. Commun. 10, 5708.

Rad23/Dsk2 axis contributes to K48-linked chain specificity of the proteasome.” Mol.
Cell 66, 485-502.

   26

Basic Medical Sciences / PROJECT

Project Leader

Hikari YOSHITANE

Hikari Yoshitane has been theleader of the Circadian Clock
Laboratory since 2021. Hestarted studying the circadianclock under the supervision ofProf. Yoshitaka Fukada in the
Department of Biophysics andBiochemistry, Graduate Schoolof Science, at the University ofTokyo. He received his Ph.D in2009 and continued his research
as an Assistant Professor in the
Fukada laboratory from 2009 to
2021. His main research interest
is to understand the molecularmechanisms of how the circadianclock oscillates autonomouslywith a period of 24 hours. He isinterested in cellular input signals
into the circadian clock andphysiological outputs from theclock. This research should help
develop novel medical treatment
strategies for many circadianclock- related diseases including
aging.

Circadian
Clock
Laboratory HP: https://www.igakuken.or.jp/project/detail/circadian.html

Staff
Researchers
Nobuhiro KURABAYASHI
Naomi NIHONMATSU
Tomoko TANAKA
Shingo HIROKI
Yuki KATO
Kyohei UEMOTO

Research Assistants
Arisa KURABAYASHI
Visiting Scientist
Yoshitaka FUKADA
Miho YOSHIMURA

Students
Yuta OTOBE
Satoshi KAWAKAMI
Etsuko MITSUYOSHI
Shunsuke ITOTaiki MORIMURA
Suzune ANDO

Research Summary<background>
Many organisms exhibit circadian rhythms, which are governedby the circadian clock. Clock genes and their encoded proteins
form transcriptional/ translational feedback loops (TTFLs) thatdrive gene expression rhythms. Disruption of the circadianclock increases the risk of developing many diseases including
insomnia, hypertension, metabolic disorders, and cancers.
<objective 1. circadian quartz>
How does the circadian clock autonomously oscillate with aperiod of about 24 hours? While the canonical TTFL model
shown below is an essential component of the clock that
regulates expression of downstream circadian genes, we believethat the critical timekeeping aspect of the clock is maintainedby protein dynamics, where protein modifications and protein

conformational changes regulate protein-protein interactions inan oscillatory manner. Thus, TTFL is required for clock read-out
and is akin to the hands of the clock, while protein dynamics may
be more similar to the quartz timekeeper in the clock. Currently
we are studying TTFL-independent protein-based clock
components to identify the quartz timing mechanism.
<objective 2. clock aging>
Disruption of the circadian clock causes dysregulation of gene
expression rhythms. This leads to functional declines including
aging-associated declines, which we refer to as “clock aging”. We
are studying the molecular mechanisms of how aging disrupts
the functional rhythms of the circadian clock and how clock
perturbations cause aging-associated symptoms.

Selected Publications
Abe et al., (2022) Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping

Yoshitane et al., (2019) “Functional D-box sequences reset the circadian clock and drive

system in mammals. Nature Communications, 13 (1): 4652.

mRNA rhythms.” Communications Biology, 2: 300.

Yoshitane et al., (2022) mTOR-AKT signaling in cellular clock resetting triggered by

Imamura et al., (2018) “ASK family kinases mediate cellular stress and redox signaling toosmotic stress. Antioxidants & Redox Signaling, 37(10):631.

circadian clock.” Proc. Natl. Acad. Sci. USA, 115(14): 3646-3651.

Hiroki et al., (2022) Molecular encoding and synaptic decoding of context during salt

Terajima et al., (2017) “ADARB1 catalyzes circadian A-to-I editing and regulates RNA

chemotaxis in C. elegans. Nature Communications, 13(1): 2928.

rhythm.” Nature Genetics, 49(1): 146-151.

Masuda et al., (2020) “Mutation of a PER2 phosphodegron perturbs the circadianphosphoswitch.” Proc. Natl. Acad. Sci. USA, 117(20): 10888-10896.

27   

Biomembrane
Laboratory HP: https://www.igakuken.or.jp/biomembrane/english.html

Laboratory HeadKohji KASAHARA

Kohji Kasahara has been thehead of the Laboratory ofBiomembranes at TMIMS
since 2020. He obtained a BSc
in Chemistry from the Tokyo
Institute of Technology in 1986, a
MSc in 1988, and a PhD from the
University of Tokyo in 1992. After
graduating, he worked at TMiMS
as a research scientist from1992 to 2003, as an independentscientist from 2003 to 2005, as aproject subleader from 2005 to
2010, and as a team leader from2010 to 2020. He also worked
at PRESTO, Japan Science andTechnology Agency from 2001 to
2005.

Staff
Researchers
Kiyoshi OGURA
Tetsuya HIRABAYASHI
Keisuke KOMATSUYANorihito KIKUCHI

Students
Mai KAWAGUCHI
Tatsuki ANJO

Research Summary
We are studying the function of lipid rafts. Lipid rafts are dynamic
assemblies of glycosphingolipids, sphingomyelin, cholesterol,and proteins that can be stabilized in microdomains on cellsurfaces. They are involved in the regulation of a number ofcellular processes including axonal guidance, cellular migration,and blood clot formation and retraction.
In order to understand how lipid rafts receive external signals andtransduce them to internal changes, we have been identifying
protein interactions of glycosphingolipids in cerebellar granulecells (CGC) from the nervous system, and in platelet cells fromthe blood.
In cerebellar granule cells we found that anti-ganglioside GD3
antibodies co-precipitate the GPI-anchored neural cell adhesion
molecule TAG-1, the src-family kinase Lyn, its substrate Cbp,
and the trimeric G protein Goα. TAG-1 is important for axonal

signals through interactions with Lyn/Cbp proteins found inganglioside GD3-rich rafts of CGC. We further found that thechemokine SDF-1α triggers the chemoattraction of cerebellar
granule cells during cerebellar development. SDF-1α stimulates
GTPγS binding to Goα, and causes Goα translocation to lipid
rafts, leading to growth cone collapse of CGC. Phosphacan, achondroitin sulfate proteoglycan, acts as a barrier to migration of
TAG-1-expressing CGC.
In blood platelets, sphingomyelin-rich lipid rafts are important for
both blood clot formation and retraction through interaction withfibrin. We have identified a factor XIII-dependent fibrin-integrin α
IIbβ3-myosin axis in sphingomyelin-rich membrane rafts that is
important in clot retraction.

guidance, and cellular migration. However, GPI anchors have no
direct contact with the cytoplasm so it was unclear how TAG1 activation causes internal cellular changes required for axonal
guidance or migration. We demonstrated that TAG-1 transduces

Selected Publications
Komatsuya K et al. (2022) “Phosphacan acts as a repulsive cue in murine and rat

Kasahara K, et al. (2010) “Impaired clot retraction in factor XIII A subunit-deficient mice.”

cerebellar granule cells in a TAG-1/GD3 raft-dependent manner” J Neurochem 163(5)Blood 115, 1277-1279.

375-390.

   28

Yuyama K, et al. (2007) “Translocation of activated heterotrimeric G protein Gαo to

Komatsuya K et al.(2020) “Function of Platelet Glycosphingolipid Microdomains/Lipid

ganglioside-enriched detergent-resistant membrane rafts in developing cerebellum.”

Rafts.” Int. J. Mol. Sci. 21(15) :5539.

J.Biol.Chem. 282, 26392-26400.

Kasahara K, et al. (2013) “Clot retraction is mediated by factor XIII-dependent fibrin-αIIbβ3-

Kasahara K, et al. (2000) “Involvement of gangliosides in GPI-anchored neuronal cell

myosin axis in platelet sphingomyelin-rich membrane rafts.” Blood 122, 3340-3348.

adhesion molecule TAG-1 signaling in lipid rafts.” J.Biol.Chem. 275, 34701-34709.

Primary-cultured cells treated with α-synuclein pre-formed fibrils were stained with
anti-tau (green) and anti-phosphorylated α-synuclein (red). Nuclei were stained withDAPI (blue).

Brain&
Neurosciences

PROJECT / Brain & Neurosciences

Project Leader

Masato HASEGAWA

Masato Hasegawa, the Headof Department of Brain and
Neurosciences, studies themolecular pathogenesis
and progression ofneurodegenerative diseases.
He started working on
Alzheimer’s disease at Yasuo
Ihara’s lab in 1988 where heidentified phosphorylation andubiquitination sites in tau. In
1995, he joined Michel Goedert’s
lab at MRC LMB where heand others demonstrated thatalpha-synuclein is the major
component of filamentous
inclusions in Parkinson’s disease
and dementia with Lewy
bodies. He next joined Takeshi
Iwatsubo’s group in 1999 where
he identified phosphorylation
and ubiquitination of alphasynuclein. In 2006, while at theTokyo Metropolitan Instituteof Psychiatry, he collaborated
with Tetsuaki Arai and foundthat phosphorylated TDP-43
accumulates in frontotemporaldementias and amyotrophic
lateral sclerosis. More recently,
he has been studying the prionlike spread of neurodegenerative
disease-associated proteins.

Dementia
Research
Laboratory HP: https://www.igakuken.or.jp/dementia/

Staff
Researchers
Takashi NONAKA
Genjiro SUZUKI
Yoshiki TAKAMATSU
Masami SUZUKAKE
Fuyuki KAMETANI
Ito KAWAKAMI

Research Assistants
Reiko OOTANIMarina TAHIRA

Students
Mina TAKASE
Shohei TAKAKI
Yuta SATO
Syunsuke KANNO

Research Summary
Many neurodegenerative diseases are associated withintracellular amyloid-like protein pathologies, such as tau in
Alzheimer’s disease (AD), α-synuclein in dementia with Lewy
bodies (DLB) and TDP-43 in amyotrophic lateral sclerosis (ALS)

and frontotemporal dementias (FTD). Importantly, the distribution
and spread of these proteins closely correlates with clinicalpresentation and disease progression.

We have been investigating these intracellular pathological proteinsprepared in these diseases, immuno-histochemically, ultrastructurally, andbiochemically using liquid chromatography with tandem mass spectrometry(LC/MS/MS).

In collaboration with Michel Goedert and Sjors Scheres in LMB and the Japan
brain bank network (JBBN), we determined the structures of pathologicaltau and alpha-synuclein filaments from brains of patients with corticobasal
degeneration (CBD) and multiple system atrophy. We further identified
numerous post-translational modifications in these filamentous assemblies.
We demonstrated that injection of aggregate recombinant tau filaments into
wild-type mice seeded the aggregation of endogenous murine tau, leading to
the spread of aggregates into distinct brain areas. In addition, we generated
two different types of alpha--synuclein fibrils from identical wild-type alpha-synuclein monomers under different conditions and showed that these fibrils
have different prion-like ablilities to convert endogenous soluble alpha-synuclein monomers into amyloid-like fibrils.

Selected Publications
Yang Y, et al. (2022) “Structures of α-synuclein filaments from human brains with Lewy

Shi Y, et al. (2021) “Structure-based classification of tauopathies.” Nature. Sep 29. Online

pathology”. Nature. 610(7933):791-795.

ahead of print. (Oct.14)

Schweighauser M, et al. (2022) “Age-dependent formation of TMEM106B amyloid

Zhang W, et al. (2020) “Novel tau filament fold in corticobasal degeneration.” Naturefilaments in human brains”. Nature. 605(7909):310-3148.

Apr;580(7802):283-287.

Arseni D, Hasegawa M, et al. (2022) “Structures of TDP-43 filaments from amyotrophic 1

Masuda-Suzukake M, et al. (2020) “Dextran sulphate-induced tau assemblies cause

lateral sclerosis with frontotemporal lobar degeneration”. Nature 601(7891):139-143.

endogenous tau aggregation and propagation in wild-type mice.” Brain Communications

Tarutani A, et al. (2022) Ultrastructural and biochemical classification of pathogenic tau,α-synuclein and TDP-43. Acta Neuropathol. 143(6):613-640.

Tarutani A, et al. (2021) “Human tauopathy-derived tau strains determine the substrates
recruited for templated amplification.” Brain. Sep 4;144(8):2333-2348.
Hosokawa M, et al. (2021) “Development of a novel tau propagation mouse model
endogenously expressing 3 and 4 repeat tau isoforms.” Brain. Sep 13:awab289.

   30

Jul 8;2(2):fcaa091.
Suzuki G, et al. (2020) “α-Synuclein strains that cause distinct pathologies differentiallyinhibit proteasome.” eLife. Jul 22;9:e56825.
Schweighauser M, et al. (2020) “Structures of α-synuclein filaments from multiple
system atrophy.” Nature Sep; 585(7825):464-469 .

Brain & Neurosciences / PROJECT

Project Leader

Minoru SAITOE

Minoru Saitoe is the vice-directorof TMIMS, the head of the
Learning and Memory Project,
the director of the Center for
Basic Technology Research,
and a visiting professor atTokyo Metropolitan University.
Dr. Saitoe received his B.A.
in Organic Chemistry from
Osaka University, his M.S. in
Biochemistry from the Tokyo
Institute of Technology, and
his Ph.D. from the University ofTokyo for studying physiological
functions of gap junctions during
Ascidian neural development.
Currently, his research focus is toelucidate mechanisms involved
in Drosophila learning andmemory and synaptic plasticity.
He is especially interested inglial-neuron networks, functional
diversity of the monoamine
system, and age-related memory
impairments. Other interests
include the molecular andneural bases of psychologicalphenomenon such as empathy
and causality.

Learning
andMemoryLaboratory HP: https://www.igakuken.or.jp/memory/

Staff
Researchers
Kohei UENO
Tomoyuki MIYASHITA
Motomi MATSUNO
Shintaro NAGANOSYoshinori SUZUKI
Takahiro ISHIKAWA

Postdoctoral fellows
Hiroshi KUROMI
Research Assistants
Saki KOMIYA
Takae HASEGAWA
Tomoko TAKAMISAWA
Kayoko GOTO
Yayoi ONODERA

Students
Maximiliano
Martinez-Cordera
Hinako MURATANI

Research Summary
Memories define us and mold our personalities. Using genetic
tools, we have identified genes and neural substrates required
for memory-associated behaviors in Drosophila. We investigate
when, where and how memory-associated gene products
function to produce memory-based behaviors and how memory
mechanisms are affected by physiological changes such asaging.
In addition to behavioral and genetic approaches, we use in vivo
and ex vivo imaging techniques to characterize physiologicalproperties of memory-associated neural networks. Our goal
is to understand how the brain forms associations between
specific sensory signals and positive and negative preferences,
how these associations are stored in the brain in neural memory
networks, and how they are later recalled at appropriate times.
We further aim to understand how memory-associated genes
and neuromodulatory systems regulate function of these
networks.

Lower left, schematic diagram of our in vivo imaging set-up. A living fly is fixedunder a microscope and can be exposed to both odors and electrical shocks.
Neuronal activity can be observed during formation, storage, and retrieval of odorshock associative memories. Lower right, in our ex vivo imaging set-up, we canmake artificial memories in cultured brains by stimulating odor and shock sensory
pathways.

Selected Publications
Ueno K et al. (2020). “Carbon monoxide, a retrograde messenger generated in post

Matsuno M, et al. (2015) “Long-term memory formation in Drosophila requires training-

synaptic mushroom body neurons evokes non-canonical dopamine release.” J Neurosci.

dependent glial transcription.” J. Neurosci. 35: 5557-5565.

40, 3533-3548.
Ueno K, et al. (2017) “Coincident postsynaptic activity gates presynaptic dopamine
release to induce plasticity in Drosophila mushroom bodies.” eLife, 6: e21076.
Hirano Y, et al. (2016) “Shifting transcriptional machinery is required for long-term
memory maintenance and modification in Drosophila mushroom bodies.” Nat.
Commun.7: 13471.

Yamazaki D, et al. (2014) “Glial dysfunction causes age-related memory impairment in
Drosophila.” Neuron 84: 753-763.
Hirano Y, et al. (2013) “Fasting Launches CRTC to Facilitate Long-term Memory
Formation in Drosophila.” Science 339: 443-446.
Miyashita T, et al. (2012) “Mg2+ block of Drosophila NMDA receptors is required for longterm memory formation and CREB-dependent gene expression.” Neuron 74: 887-898.

31   

PROJECT / Brain & Neurosciences

Project Leader

Yukio NISHIMURA

Yukio Nishimura, PhD has led theNeural Prosthetics Project since2017. He received a B.S. in Sports
Sciences from Nihon University, aM.S. in Education from Yokohama
National University and a PhD
from Chiba University Medical
School in 2003. He was a postdoctoral fellow at the National
Institute for Physiological Sciencein Japan from 2003 and at the
University of Washington in
the US from 2007. He started
working at the National Institutefor Physiological Science in 2011,
and then joined the faculty of
Kyoto University in 2016 as an
Associate Professor. His overall
research is in neural control ofli mb move me nts in hu ma ns
and non-human primates. Hispresent research focuses onneural mechanisms of functional
recovery after neural damage
and restoration of lost functions
using brain computer interfaces.

NeuralProsthetics
Laboratory HP: https://www.igakuken.or.jp/english/project/detail/neuroprosth1.html
https://neural-prosthetics.jp/

Staff
Researchers
Yoshihisa NAKAYAMA
Toshiki TAZOE
Osamu YOKOYAMASho K. SUGAWARA
Michiaki SUZUKI
Postdoctoral fellows
Noboru USUDA
Hikaru NAKAGAWA

Research Assistants
Naoko YOSHIDA
Shoko HANGUI
Yukie AIZAWA
Sachiko SHIMAKAWA
Sumiko URA
Nao MOTOYANAGI
Tsuta UCHIDA

Students
Kei OBARA
Kouichi URAMARU
Kokoro KAWAMURA

Research Summary
Our goal is to conceive of innovative ideas for neuro-rehabilitationof lost functions after nervous system damage, and to translatethese ideas into clinical applications capable of improving thequality of life for individuals with neural damage.
Specifically, we are developing a neural interface known as an“artificial neuronal connection (ANC)”. This ANC bridges spinal
lesions by connecting supra-spinal systems with spinal networks
distal to the lesion to restore lost functions. We are conducting

clinical trials to assess the effectiveness of ANCs in restoring
motor function in paralyzed patients. We are also investigatingneural changes that occur during recovery.
Depression impedes, and motivation enhances, functional
recovery after neuronal damage. Although higher motivation
seems to boost motor performance and recovery, neuralsubstrates underlying this psychological effect remains unknown.
We are identifying these neuronal substrates using humans andanimal models.

Selected Publications   32

Kato K, et al. (2019) “Bypassing stroke-damaged neural pathways via a neural interface

Nishimura Y, et al. (2013) “Spike-timing-dependent plasticity in primate corticospinal

induces targeted cortical adaptation.” Nature Communications. 10(1):4699.

connections induced during free behavior.” Neuron 80(5):1301-1309.

Umeda, et al., (2019) “The somatosensory cortex receives information about motor

Nishimura Y, et al. (2009) “A subcortical oscillatory network contributes to recovery of

output.“ Science Advances., 5(7):eaaw5388.

hand dexterity after spinal cord injury.” Brain 132(Pt 3):709-721

Sawada M, et al. (2015) “Function of the nucleus accumbens in motor control during

Nishimura Y, et al. (2007) “Time-dependent central compensatory mechanisms of finger

recovery after spinal cord injury.” Science 350(6256):98-101.

dexterity after spinal cord injury.” Science. 318(5853):1150-1155

Brain & Neurosciences / PROJECT

Project Leader

Hiroshi SAKUMA

Hiroshi Sakuma has been theleader of the Child Brain Projectsince 2015. He graduated andobtained his MD (1993) andPhD (2005) degrees at Tokyo
Medical and Dental University
and pursued training in pediatricneurology at the National Centerof Neurology and Psychiatry. He
started his research activities onneuroimmunology in National
Institute of Neuroscience under
the supervision of Prof. Sachiko
Miyake in 2010, and also wasinvolved in the Health Labour
Sciences Research on virusassociated acute encephalopathy
since 2010. He has been working
at Tokyo Metropolitan Instituteof Medical Science since 2012.
His current research interests
include 1) pathomechanismsof virus-associated acuteencephalopathies including
febrile infection-related epilepsy
syndrome, 2) biomarkers forpediatric immune-mediatedneurological diseases, and 3)
making international consensus
on pediatric autoimmune
neurological diseases.

Child
Brain
Laboratory HP: https://www.igakuken.or.jp/development/

Staff
Researchers
Tadayuki SHIMADA
Kuniko KOHYAMA

Visiting scientists
Hiroko TADA
Ai HOSHINO
Tomonori SUZUKI
Naoyuki TANUMA
Masaharu HAYASHI
Research Assistants
Mariko OZAKI

Students
Asako HORINO
Hiroya NISHIDA
Kengo MORIYAMA
Motoshi FUJITA
Rie NAKAI
Takayuki MORI

Research Summary
Our research focuses on autoimmune and inflammatoryneurological diseases (AINDs) in childhood. They are significant
social burden because of poor prognosis and high mortality. We
have established a sustainable platform (a multicenter registry ofpatients and sample repository) for a prospective cohort studies
on AINDs based on nationwide collaborative study. We perform
multi-omics analysis of biomarkers including inflammatory
mediators, microRNAs, and metabolites. This multifaceted
approach using high-throughput methods enables us to explore
novel molecular targets associated with AINDs.
Recent studies have highlighted the importance of glial cells in
the pathogenesis of AINDs. Our transgenic animal models are
expected to shed new light on how gilal cells contribute to thepathomechanisms of AINDs by regulating brain metabolism andinflammation, and also provide a rationale for a novel therapeuticstrategy.

3. A utoimmune encephalitis and acquired demyelinating
syndromes
4. Autoantibodies associated with neurological diseases
5. New biomarkers for pediatric immune-mediated neurologicaldiseases

Figure Pathomechanisms of inflammatory and autoimmune neurological diseases
Multiple sclerosis has been regarded as CD4 T-cell mediated disease, in which
autoreactive T cells are activated, proliferate, migrate into brain, and cause myelin

Our main research areas include:
1. Pathomechanisms of virus-associated acute encephalopathies
2. The role of inflammation in febrile infection-related epilepsy
syndrome

damage. Autoimmune encephalitis is caused by autoantibodies against neuronalsurface antigens, produced by plasma cells in both periphery and central nervous
system. Although the pathogenesis of virus-associated encephalopathy has not been
fully elucidated, pro-inflammatory cytokines and chemokines are highly increased inbiofluids, suggesting cytokine-mediated mechanisms.

Selected Publications
Nosadini M et al. (2021) “Use and safety of immunotherapeutic management of

Horino A, et al. (2021) “Intrathecal dexamethasone therapy for febrile infection-related

N-methyl-d-aspartate receptor antibody encephalitis: a meta-analysis.” JAMA Neurol.

epilepsy syndrome.” Ann. Clin. Transl. Neurol. 8:645-655.

78:1333-1344.
Nosadini M et al. (2021) International consensus recommendations for the treatment ofpediatric NMDAR antibody encephalitis. Neurol Neuroimmunol Neuroinflamm. 8:e1052.

Suzuki T, et al. (2020) “Extracellular ADP augments microglial inflammasome and NF-KB
activation via the P2Y12 receptor.” Eur. J. Immunol. 50:205-219.
Sakuma H, et al. (2015) “Intrathecal overproduction of proinflammatory cytokines

Nishida H et al. (2021) “Evaluation of the diagnostic criteria for anti-NMDA receptor

and chemokines in febrile infection-related refractory status epilepticus.” J. Neurol.

encephalitis in Japanese children.” Neurology. 50:e2070-e2077.

Neurosurg. Psychiatr. 86:820-822

33   

PROJECT / Brain & Neurosciences

Project Leader

Takashi SHICHITA

Takashi Shichita has been the
project leader of the Stroke
Renaissance Project since 2017.
After graduating from the Facultyof Medicine, Kyushu University
in 2004, he practiced internal
medicine and was affiliatedwith the CerebrovascularCenter, Kyushu Medical Center.
He conducted research at
Kyushu University and Keio
University and received a Ph.D
in 2010 from Kyushu University
for clarifying molecular andcellular mechanisms underlying
inflammation after ischemic
stroke. His current interest is toclarify the precise molecularmechanisms for the neural repair
in brains damaged by strokeand dementia. His group willdevelop therapeutic methods
which sustain the reconstructionof neural circuits for accelerated
recovery from stroke anddementia.

StrokeRenaissanceLaboratory HP: https://www.igakuken.or.jp/stroke-renaiss/

Staff
Researchers
Seiichiro SAKAI
Jun TSUYAMA

Research Assistants
Yoshiko YOGIASHI
Kumiko KURABAYASHI

Students
Koutaro NAKAMURA
Akari NAKAMURA
Kento OTANI

Research Summary
Stroke is a common cause of severe disability and deathworldwide; however, few therapeutic agents have been shown
to improve the neurological deficits of stroke patients.
In this Project, we are studying the detailed molecularmechanisms underlying the neural repair after stroke anddementia. New research methods and techniques whichhave been recently developed in the field of immunology or
neuroscience are allowing us to investigate the precise processof inflammation and repair in the injured brain after strokeand dementia. The purpose of our project is to develop a new
therapeutic method for promoting the recovery of neurological
function in patients with cerebrovascular diseases.

Sterile Inflammation After Ischemic Stroke“What triggers neural repair after stroke?”We have identified peroxiredoxin family proteins as DAMPs (damage associatedmolecular patterns) which trigger post-ischemic inflammation (Nat. Med. 2012). DAMPs
induce IL-23 production from infiltrating macrophages and neutrophils, and thissustains the inflammation after ischemic stroke by promoting IL-17 production of γδTlymphocytes (Nat. Med. 2009). Cerebral post-ischemic inflammation resolves several
days after the stroke onset. The clearance of DAMPs from ischemic brain through
MSR1, a scavenger receptor, plays a pivotal role in the resolution of sterile inflammation
after ischemic stroke (Nat. Med. 2017). Currently, we are studying how cerebral postischemic inflammation switches into the process of neural repair.

Selected Publications   34

Nakamura K, et al. (2021) “Extracellular DJ-1 induces sterile inflammation in the ischemic

Shichita T, et al. (2012) “Peroxiredoxin family proteins are key initiators of post-ischemic

brain.” PLOS. Biol. 19(5):e3000939.

inflammation in the brain.” Nat. Med. 18(6): 911-917.

Shichita T, et al. (2017) “Mafb prevents excess inflammation after ischemic stroke by

Shichita T, et al. (2009) “Pivotal role of cerebral interleukin-17-producing gammadelta T

accelerating clearance of danger signals through MSR1.” Nat. Med. 23(6): 723-732.

cells in the delayed phase of ischemic brain injury.” Nat. Med. 15(8):946-950.

Brain & Neurosciences / PROJECT

Project Leader

Chiaki OHTAKA-MARUYAMA

Chiaki Ohtaka-Maruyama
graduated with a Ph.D. fromthe University of Tokyo witha diploma in Biology. After
postdoctoral training at NEI,NIH (Bethesda, MD, USA) and
RIKEN(Wako), she became
Research Scientist in 2006 at theTokyo Metropolitan Institute for
Neuroscience (the predecessorof Tokyo Metropolitan Instituteof Medical Science). She started
her research in the neuraldevelopment field. She has been
the project leader since April
2019. Her research focuses onunderstanding the molecular andcellular mechanisms of corticaldevelopment and evolution.
In particular, she is interested
in how mammalian six-layer
structure was developed
during evolution. Using timelapse imaging and functional
analyses of subplate neurons,
she found this cell population's
novel function in regulating radial
neuronal migration.

Developmental
Neuroscience
Laboratory HP: https://www.igakuken.or.jp/stroke-renaiss/

Staff
Researchers
Keisuke KAMIMURA
Takuma KUMAMOTO
Yumiko HATANAKA
Keiko MORIYA-ITO
Yasuhiro MATSUMURA

Research Assistants
Kumiko HIRAI
Katsuko TAKASAWA
Aiko ODAJIMA
Yoshiko TAKAHASHI
Ayako MORITA
Yukiko MAKINO

Students
Hitomi ACHIWA
Ayumu MORIOKA
Kyosuke WADA
Haruka NOMURA
Yusuke SUGITSA
Mayu OZAKI
Ryoka KATAYAMA
Xianghe SONG
Yurika NOGUCHI

Research Summary
Mechanisms of Neural Network ormation: Neocorticaldevelopment and synapse formation
How does the mammalian neocortex acquire the unique sixlayered structure considered to be the structural basis for theremarkable evolution of complex neural circuits? We focus onsubplate (SP) neurons that develop and mature too early duringcortical development but disappear postnatally to approach thisquestion. Recently, we found that SP neurons play an essential
role in radial neuronal migration via direct interaction with young
migrating neurons. Moreover, the SP layer is surrounded by a rich
extracellular matrix (ECM), suggesting that it may be an importantsignaling center for mammalian corticogenesis. Functional
elucidation of the SP layer should lead to a better understandingof brain development during evolution.
“We are interested in the roles of the subplate later in thedevelopment of the cerebral cortex. It suggests that this transientcell population plays a crucial role as a symbolic “control tower”
during neocortical formation and also adult cortical function.”

Selected Publications
Kumamoto T and Ohtaka-Maruyama C (2022) “Visualizing Cortical Development andKamimura K et al. (2019) “The HSPG Glypican Regulates Experience-Dependent

Evolution: A Toolkit Update” Front Neurosci., 16,876406

Synaptic and Behavioral Plasticity by Modulating the Non-Canonical BMP Pathway.” Cell

Miyatake S, et al. (2021) “Polymicrogyria: a novel ATP1A3-related phenotype.” Science
Advances, 7(13): eabd2368.
Ohtaka-Maruyama C (2020) “Subplate neurons as an organizer of mammalian
neocortical development. ”Front. Neuroanat. 14, 8.
Nomura T, et al. (2020) “Changes in Wnt-dependent neuronal morphology underlie theanatomical diversification of neocortical homologs in amniotes.” Cell Reports, 31,107592.

Reports, 28, 3144-3156.
Ohtaka-Maruyama C, et al. (2018) “Synaptic transmission from subplate neurons controls
radial migration of neocortical neurons.” Science 360, 313-317
Ohtaka-Maruyama C, et al. (2013) “RP58 regulates the multipolar-bipolar transition of
newborn neurons in the developing cerebral cortex.” Cell Reports, 3, 458-471
Kamimura, K, et al. (2013) “Perlecan regulates bidirectional Wnt signaling at the
Drosophila neuromuscular junction.” J Cell Biol. 200, 219-233.

35   

MR image of the brain. In this instance, slight atrophy was detected in the left frontal
lobe and around the gutter.

Psychiatry&
Behavioral
Sciences

PROJECT / Psychiatry & Behavioral Sciences

Project Leader

Makoto ARAI

Makoto Arai has been working
as a reader in the schizophrenia
research project in the Institutesince April of 2015. After obtaining
Master's and Doctoral Programof the Department of Biological
Science and Technology,
Faculty of Industrial Science andTechnology, Tokyo Universityof Science. He received Ph.D.
of Engineering from Tokyo
University of Science in 2002.
He shifted his focus to research
for molecular mechanismsof schizophrenia under thesupervision of Dr. Masanari
Itokawa as a postdoctoral
fellow position in 2002 and has
been working on how genetic
and environmental factors
are involved in schizophrenia.
Currently, he is interested inmechanisms of glycation andoxidative stress associatedwith phenotypes of psychiatricdisorders during life stage.
Advancement of studies madeusing specific biomarkers will
highlight the innovative ideas
underlying recovery frompsychiatric disorders.

Schizophrenia
Research
Laboratory HP: https://www.igakuken.or.jp/schizo-dep/english.html

Staff
Researchers
Masanari ITOKAWA
Yasue HORIUCHI
Kazuya TORIUMI
Hiroaki ISHIDA

Research Assistants
Ikuyo KITO
Nanako OBATA
Izumi NOHARA
Mai HATAKENAKA
Tomoko INOUE

Students
Yasuhiro MIYANO
Koichi TABATA
Mai ASAKURA
Tianran WANG
Kyoka IINO
Mayuko MASADA
Azuna OZAWA
Yasufumi TOMITA

Research Summary
Profiling of the peripheral metabolic system is a viableschizophrenia research strategy that can lead to earlier diagnostic
methods, elucidation of molecular mechanisms, and novel
strategies for the prevention and treatment of schizophrenia.
We focus on, 1) developing individualized medicine for treating
schizophrenia, 2) investigating factors involved in disease
onset, and 3) understanding the molecular pathology byusing biomarkers to overcome the barrier of heterogeneity.
Our research outcomes will be applied to drug developmentby establishing a new biomarker-based field of research inmolecular psychiatry. Data obtained from metabolomics,
genomics, induced pluripotent stem (iPS) cell models, animalmodels, post-mortem brain analyses, neuropsychology, andgenetic counseling research will be consolidated to elucidate
the genetic and environmental factors relevant to psychiatricdisorders such as schizophrenia.

The biomarker-based approach is an innovative and creative strategy for identifying
the metabolic changes associated with schizophrenia, independent of conventional
pathological hypotheses. Verification in cellular and animal models can shed light on
the molecular mechanisms underlying the utility of naturally-derived substances in
trading schizophrenia, and is expected to lead to the future development of muchsafer treatments and prophylactic methods.

Selected Publications
Suzuki K, et al. (2022) “Role of advanced glycation end products in the longitudinal

Toriumi K, et al. (2021) “Combined glyoxalase 1 dysfunction and vitamin B6 deficiency

association between muscular strength and psychotic symptoms among adolescents.”

in a schizophrenia model system causes mitochondrial dysfunction in the prefrontal

Schizophrenia (Heidelb). 8(1):44.

cortex.”Redox Biology 45: 102057.

Toriumi K, et al. (2022) “Role of glyoxalase 1 in methylglyoxal detoxification-the broad

Yoshikawa A, et al. (2021) “Dysregulation of post-transcriptional modification by copy

player of psychiatric disorders.” Redox Biol. 49:102222.

number variable microRNAs in schizophrenia with enhanced glycation stress.” Transl

Iino K, et al. (2021) “AKR1A1 Variant Associated With Schizophrenia Causes Exon
Skipping, Leading to Loss of Enzymatic Activity.” Front Genet. 12:762999.
Miyashita M, et al. (2021) “Fingertip advanced glycation end products and psychotic
symptoms among adolescents.” NPJ Schizophr. 7:37.

Psychiatry. 11:331.
Kobori A, et al. (2021) “Advanced glycation end products and cognitive impairment inschizophrenia.” PLoS One. 16: e0251283.
Toriumi K, et al. (2021) “Vitamin B6 deficiency hyperactivates the noradrenergic system,
leading to social deficits and cognitive impairment.” Transl Psychiatry. 11: 262.

   38

Psychiatry & Behavioral Sciences / PROJECT

Project Leader

Makoto HONDA

Makoto Honda has been theleader of the Sleep Disorders
Project since 2009. After
graduation from School of
Medicine, University of Tokyo in
1989, he worked as a psychiatrist
in Tokyo University Hospital,
Tokyo Metropolitan Matsuzawa
Hospital in parallell with thetraining of molecular genetics
under Prof. Tatsuhiko Kodama.
He received Ph.D in 1998 fromthe Graduate School of Science,
Univ. of Tokyo. In 2001 after the
discovery of hypocretin/orexin
loss in narcolepsy, he moved
to the Narcolepsy Center in
Stanford University, USA, as a
post-doctoral student / research
fellow. Since then he has beenworking in sleep research
fields. His primary interest is tounderstand the pathophysiology
of sleep disorder narcolepsy andidiopathic hypersomnia and tofind better markers/treatment
options for them. He also works
as a sleep physician to pushforward clinical research.

Sleep
DisordersLaboratory HP: https://www.igakuken.or.jp/sleep/

Staff
Researchers
Taku MIYAGAWA
Akiyo NATSUBORI
Yoshiki MATSUDA
Tohru KODAMA
Haruo OKADO

Research Assistants
Takashi KOJIMA
Yasuko SEKI
Yoshiko HONDA
Hiroko SHIMBO
Kyoko OOFUSA
Nobuyuki OZAWA
Takiko SHINOZAKI

Visiting Scientist
Mihoko SHIMADA
Students
Momoka MIYAZAWA

Research Summary
Our goal is to find the causes and develop better treatments for
Narcolepsy and Hypersomnia.
Narcolepsy is a sleep disorder of abnormal intrinsic sleep-wakeregulation, resulting in unique symptoms including frequentlapses into sleep, nocturnal sleep instability, and REM sleep
related manifestations such as cataplexy (abrupt loss of muscle
tone triggered by emotion), sleep paralysis, and hypnagogic
hallucination.

based treatments for sleep disorders, including narcolepsy. We
are trying to elucidate the pathophysiology of narcolepsy withmultifaceted problems to improve the QOL of hypersomnia
patients.

Narcolepsy is associated with a deficiency of wakepromoting orexin/hypocretin producing neurons localized in
the hypothalamus, and virtually all the patients carry humanleukocyte antigen (HLA)-DQB1*06:02.
We are trying to solve the mystery of narcolepsy
Narcolepsy is associated with a variety of physical and psychiatriccomorbid conditions. Since appropriate wakefulness is essential
for higher brain functions, abnormal sleep-wake regulation canlead to various associated features. Despite the progress in
sleep research fields, we currently have inadequate symptom-

Selected Publications
Natsubori A et al. (2022) Serotonergic neurons control cortical neuronal intracellularenergy dynamics by modulating astrocyte-neuron lactate shuttle iScience 26, 105830,
2023 doi: 10.1016/j.isci.2022.105830.
Miyagawa T, et al (2022) A rare genetic variant in the cleavage site of prepro-orexin geneis associated with idiopathic hypersomnia. npj Genomic Medicine 7:29 [2022/4/12]
Honda M, et al (2022) Low carnitine palmitoyltransferase 1 activity is a risk factor fornarcolepsy type 1 and other hypersomnia. Sleep 45:zsac160
Miyagawa T, et al (2022) A variant in orexin receptor-2 is associated with self-reported

Psychiatry Clin Neurosci 75:149-151
Natsubori A, et al (2020) In vivo state-dependent dynamics of cellular energy status incortical neurons. Communications Biol 3: 491
Shimada M, et al (2020) Epigenome-wide association study of narcolepsy-affected
lateral hypothalamic brain and overlapping DNA methylation profiles between
narcolepsy and multiple sclerosis. Sleep 43:zsz198
Shimada M, et al (2020) Metabolome analysis using cerebrospinal fluid from narcolepsy
type 1 patients. Sleep. 43:zsaa095.

daytime sleepiness in the Japanese population. J Hum Genetics 67:377-380
Honda M, et al (2021) Evaluation of pathological sleepiness by Multiple Sleep Latency
Test and 24-hour polysomnography in patients suspected of idiopathic hypersomnia.

39   

PROJECT / Psychiatry & Behavioral Sciences

Project Leader

Kazutaka IKEDA

Kazutaka Ikeda, the head of
Department of Psychiatry and
Behavioral Sciences since 2015,
has been the leader of the
Addictive Substance Projectsince 2005. He graduated Facultyof Engineering, the Universityof Tokyo in 1989. After that, hestudied under Dr. Kenji Sobue,
Dr. Masayoshi Mishina and Dr.
Toshiro Kumanishi as a graduate
student. He received Doctor of
Medical Science in 1995 from
Graduate School of Medical
Science, Niigata University. He
started to work at RIKEN as a
researcher under the supervisionof Dr. Masao Ito, Dr Ryoji Yanoand Dr Hiroaki Niki in 1995. He
moved to Tokyo Metropolitan
Institute of Psychiatry in 2000
and has leaded a project teamsince 2002. His current interest is
to improve treatment, prevention,and understanding of addiction,
pain, and developmental
disorders through revealing of
mechanisms underlying addictive
substance effects.

Addictive
Substance
Laboratory HP: https://www.igakuken.or.jp/abuse/

Staff
Researchers
Soichiro IDE
Shinya KASAI
Daisuke NISHIZAWA
Masayo FUJITA
Seii OHKA
Hiroko KOTAJIMA
Yuki MORIYA

Research Assistants
Yoko HAGINO
Junko HASEGAWA
Etsuko KAMEGAYA
Yuiko IKEKUBO
Yuki SERITA
Yuko EBATA
Kyoko NAKAYAMA

Students
Yoshihisa KATO
Aimi YAMAGISHI
Masako MORII
Yasuharu YAMAGUCHI
Masato OKITSU
Joei ZOU
Ryunosuke MARUYAMA
Jun ARAIDA
Yuna KANG
Ririka MORIMOTO
Futaba UMEMURA

Research Summary
Addiction to various substances (e.g., drugs, alcohol, andtobacco) and behaviors (e.g., internet and gambling) is a serious
public health problem. The use of illegal drugs has been
increasing in Japan in recent years. Thus, preventing and solving
problems that are related to addiction are important.
Some addictive drugs are also widely used as analgesics andfor the treatment of developmental disorders. Some moleculesthat are involved in the actions of addictive drugs may be shared
between analgesia and developmental disorders. The goals of
our project are the following:(1) Developing novel treatments for addiction and prevention.
We study action mechanisms of opioids, dopamine, andhallucinogens such as phencyclidine to reveal the onsetof addiction using several mouse models and behavioral
pharmacological study. In parallel with the basic research, we
also develop and verify a scale to addiction severity.
(2) Improving personalized pain treatment. Sensitivity of opioid
analgesics is associated with polymorphisms of several genes.
Based on the genome information, we develop personalized pain
treatment.
(3) Developing novel treatments for developmental disorders.
We mainly focus on autism and attention deficit hyperactivity

disorder (ADHD). In our project, tuberous sclerosis complex 1 and2 hetero knockout mouse and dopamine transporter knockout
mouse are mainly used as models of autism and ADHD,
respectively. We are finding novel treatments for autism.
Attaining these goals will make significant contributions tosociety. We seek to accomplish these goals by studying theactions of addictive drugs using molecular biological, behavioral
pharmacological, human genomic, and clinical approaches.

Selected Publications
Kotajima-Murakami H, et al (2022). “Exposure to GABAA receptor antagonist picrotoxin in

Ide S, et al. (2021) “Caenorhabditis elegans exhibits morphine addiction-like behavior via

pregnant mice causes autism-like behaviors and aberrant gene expression in offspring.”

the opioid-like receptor NPR-17.” Front Pharmacol, 12:802701

Front Psychiatry 13:821354.

with herpes zoster and enhances varicella-zoster virus-mediated fusogenic activity.” Molassociated with opioid analgesic requirements in the treatment of cancer pain.” Cansers

Pain 17:17448069211052171.

14:4692.

Kasai S, et al. (2021) “Short tandem repeat variation in the CNR1 gene associated with

Sato A and Ikeda K. (2022) “Genetic and environmental contributions to autism spectrum

analgesic requirements of opioids in postoperative pain management.” Front Genet

disorder through mechanistic target of rapamycin.” Biol Psychiatry: Glob Open Sci 2:95-

13:815089.

105.

   40

Ohka S, et al. (2021) “Heparan sulfate 3-O-sulfotransferase 4 is genetically associatedNishizawa D, et al. (2022) “Genome-wide association study identifies candidate loci

Psychiatry & Behavioral Sciences / PROJECT

Frontier ResearchLaboratory
Laboratory HP: https://www.igakuken.or.jp/frontier01/

Head researcher,
independent research group

Shinobu HIRAI

Staff
Atsushi SAKUMA
Hiroko SHIMBO

Yayoi ONODERAKeiko OOFUSASerina UCHIDA
Rei SHIRAKAWA

Nobuyuki ARUGA

Research Summary
Sugars are critical to brain function since they are the energy
source required for neurons and glial cells. Our goals are to
elucidate the dynamics of sugar movement in the brain and to
examine how alterations in sugar dynamics affect physiologicalbrain activity to cause brain diseases (Figure 1).

Sugar metabolism in the cells(by FRET Probe + Fiber photometry)
Blood vessel →Brain parenchyma(by Biosensor)

Glia

Blood vessel

Using a mouse model, we recently determined that excess sugar
consumption during adolescence is a potential contributing
factor to psychological disease (Science Advances, doi: 10.1126/
sciadv.abl6077). In these mice, excess sugar consumption
resulted in severe impairments in sugar transport from bloodvessels into the brain. In addition, the connection between sugar
metabolism and Alzheimer’s disease is so strong that Alzheimer’s
disease has been described as a third type of diabetes. Theseobservations indicate that breakdowns in metabolic pathways
and sugar homeostasis are almost certain to contribute to thedevelopment and severity of psychological and neurologicaldiseases. Our work will contribute to the development of
new drugs to improve metabolism and novel treatments forpsychological and neurological diseases.

EEG,
Behavior

Brain parenchyma→ Cells (by FRET probe)

Expression ofhigher brain function

Sugar, Amino acid, etc.
NeuronDevelopment of
new probes

Elucidation of metabolite dynamics
underlying the expression of brain functions
Figure 1. Conceptual diagram of our research. To understand the effects sugar
dynamics have on higher brain functions by identification of cells contributing to sugartransport to the brain (construction and behavioral analyses of conditional knockout mice) and analyses of intra- and extracellular sugar metabolism (using fiber
photometry, FRET probes and biosensors).

Selected Publications
Hirai S. et al. (2023) “The mouse model of intellectual disability by ZBTB18/RP58

Hirai S. et al. (2017) “AMPA glutamate receptors are essential for sensory-organ formation

haploinsufficiency shows cognitive dysfunction with synaptic impairment.” Molecularand morphogenesis in the basal chordate” PNAS 114: 3939-3944.

Psychiatry doi: 10.1038/s41380-023-01941-3.
Hirai S. et al. (2021) “High Sucrose Diets Contribute to Brain Angiopathy with Impaired
Glucose Uptake, and Psychosis-related Higher Brain Dysfunctions in Mice” Science
Advances 7: eabl6077.

41   Cardiomyocytes differentiated from human iPS cells:
Sarcomeres (red; stained by ACTININ), functional units forcontraction, and the nuclei (blue) are visualized.

Diseases&
Infection

PROJECT / Diseases & Infection

Project Leader

Fumihiko YASUIFumihiko Yasui has been theleader of the Viral Infection
Control Project since 2017. Hereceived Ph.D in 2004 from
Graduate School of Engineering,
University of Yamanashi. He
joined The Tokyo Metropolitan
Institute of Medical Science as a
postdoctoral fellow in 2004 andstarted to work on mechanismsof pathogenesis of viral
infections. He is interested in how
immunity controls viral infection,and how viruses escape fromhost defense.

Viral
Infection
Control
Laboratory HP: https://www.igakuken.or.jp/infectious/

Staff
Researchers
Michinori KOHARA
Tsubasa MUNAKATA
Daisuke YAMANE
Kenzaburo YAMAJI

Yuko TOKUNAGA
Naoki YAMAMOTO
Takahiro SANADA
Yusuke MATSUMOTO
Tomoko HONDA

Research Assistants
Asako TAKAGI
Risa KONO
Masahiko HIGA
Sakiko TOYAMAAya KOSEKI

Research Summary
Our project studies the virology, immunology, vaccinology andtherapy of incurable viral diseases. We currently focus on liverdiseases, viral acute pneumonia and dengue fever. However,the lack of suitable infection models in vitro and in vivo has
hampered the clarification of viral pathogenesis. To overcome
this problem, we have been developing various animal models
including transgenic mice, humanized mice with human liver
cells, monkeys and tree shrews. We also investigate the precise
mechanisms by which host factors regulate viral growth.

Selected Publications
Ishigaki H, et al. (2022) "An attenuated vaccinia vaccine encoding the SARS-CoV-2

Saito M, et al. (2021) “Macrocyclic peptides exhibit antiviral effects against influenza virus

spike protein elicits broad and durable immune responses, and protects cynomolgus

HA and prevent pneumonia in animal models.” Nat Commun. 12(1):2654.

macaques and human ACE2 transgenic mice from SARS-CoV-2 and its variants.” Front
Microbiol. 13:967019.
Yasui, F, et al. (2022) “Infection with the SARS-CoV-2 B.1.351 variant is lethal in aged
BALB/c mice.” Sci Rep. 12: 4150
Sanada T, et al. (2021) In press “Serologic survey of IgG against SARS-CoV-2 amonghospital visitors without a history of SARS-CoV-2 infection in Tokyo, 2020-2021.”
Journalof Epidemiology. 32(2):105-111.

   44

Honda T., et al. (2021) “Development and Characterization of a Highly Sensitive
NanoLuciferase-Based Immunoprecipitation System for the Detection of Anti-Influenza
Virus HA Antibodies.” mSphere 6(3): e01342-2
Sanada T, et al. (2019) “Avian H5N1 influenza virus infection causes severe pneumonia in
the Northern tree shrew (Tupaia belangeri).” Virology 529:101-110.

Diseases & Infection / PROJECT

Project Leader

Satoshi KOIKE

Satoshi KOIKE has been theleader of Neurovirology Projectsince 2005. He received Ph.D in
1987 from the Graduate Schoolof Medicine, the Universityof Tokyo. He started his workon poliovirus, a neurotropic
enterovirus, at Tokyo
Metropolitan Institute of Medical
Science in 1987 with Dr. Akio
Nomoto. After he stayed several
years at Institute Pasteur in Parisand National Institute for Basic
Biology in Okazaki, he began to
study on enterovirus 71 (EV71)
and other related enteroviruses
at Tokyo Metropolitan Institute of
Neuroscience in 1998. His group
identified Scavenger receptor
B2 as the receptor for EV71 andgenerated a transgenic mousemodel susceptible to EV71. His
current interest is molecularmechanism of infection andpathogenesis of enteroviruses.

Neurovirology
Laboratory HP: https://www.igakuken.or.jp/neurovirology/

Staff
Researchers
Kyousuke KOBAYASHI

Research Assistants
Ayako OKUBO
Masako UKAJI
Namiko NOMURATomoha NISHIZAWA
Minori ISHIDA
Sayaka ESAKI

Research SummaryEnterovirus 71 (EV71), a human enterovirus species A of the genus
Enterovirus within the Picornaviridae family, is known to be oneof the causative agents of hand-foot-and-mouth disease (HFMD).
HFMD is generally a mild and self-limiting disease. However, insome infants and young children, HFMD caused predominantly
Research Topics
Mechanism of Enterovirus 71 infection

by EV71 can be complicated by neurological manifestations.
Thus, EV71 infection is a serious public health concern.
Unfortunately, there is still very little information concerning EV71
pathogenesis, and vaccines or anti-EV71 drugs have yet to be
developed.
Development of an animal model for Enterovirus 71 infection

We recently found that Scavenger receptor B2 (SCARB2) is a receptor for EV71.
SCARB2 plays a central role in early stages of EV71 infection. SCARB2 is able tomediate binding of the virus at the cell surface, internalization of the virus andTransgenic mice expressing human SCARB2 are susceptible to EV71, and are a

initiation of uncoating.

useful model for the study of EV71 pathogenesis and vaccine efficacy.

Selected Publications
Miwatashi W, et al. (2022)”Mouse Scarb2 Modulates EV-A71 Pathogenicity in Neonatal

Kobayashi K, et al. (2020) “Heparan sulfate attachment receptor is a major selection

Mice.” J. Virol.,96:(15)e0056122

factor for attenuated enterovirus 71 mutants during cell culture adaptation.” PLoS

Tamura K, et al. (2022) “TAK - 021, an inactivated Enterovirus 71 vaccine candidate,

Pathog., 18:16(3)e1008428

provides cross-protection against heterologous sub-genogroups in human scavenger

Imura A, et al. (2020) “Development of an Enterovirus 71 Vaccine Efficacy Test Using

receptor B2 transgenic mice.” Vaccine,40:(24)3330-7

Human Scavenger Receptor B2 Transgenic Mice.” J. Virol., 94:(6)e01921-19

Kobayashi K, et al. (2021) “Virulence of Enterovirus A71 Fluctuates Depending on the

Kobayashi K, et al. (2018) “Amino Acid Variation at VP1-145 of Enterovirus 71 Determines

Phylogenetic Clade Formed in the Epidemic Year and Epidemic Region.” J. Virol.,95:(23)Attachment Receptor Usage and Neurovirulence in Human Scavenger Receptor B2

e0151521

Transgenic Mice.” J. Virol., 92:(15)e00681-18

45   

PROJECT / Diseases & Infection

Project Leader

Takayuki HARADA

Takayuki Harada has been thehead of the Visual Research
Project since 2011 and a visiting
professor in the Department ofOphthalmology at Tokushima
University since 2013. He
obtained his MD from Hokkaido
University School of Medicine
in 1992 and worked as a longterm fellow of the Human
Frontier Foundation at the
University of Texas Southwestern
Medical Center in 2001, and as
a molecular neuroscientist at
the Medical Research Instituteof Tokyo Medical and Dental
University in 2002, before
becoming the director of
the Molecular Neurobiology
Research Division of theTokyo Metropolitan Institute of
Neuroscience in 2004.

VisualResearch
Laboratory HP: https://www.igakuken.or.jp/retina/

Staff
Researchers
Kazuhiko NAMEKATA
Xiaoli GUO
Chikako HARADA
Takahiko NORO

Euido NISHIJIMA
Yuta KITAMURA
Naoki KIYOTA
Akiko SOTOZONO

Research Assistants
Mayumi KUNITOMO
Tomoko HARA
Students
Shuri SANADA

Research Summary
More than 1.6 million people in Japan are visually impaired
and the number of patients with conditions such as glaucoma
and diabetic retinopathy is increasing. We seek to elucidate
mechanisms involved in the onset of visual impairments such as

optic neuritis, develop a neuroprotective retinal therapy using
animal disease models, and establish methods to promote
regeneration of the optic nerve.

Apoptosis signal related kinase 1 (ASK1) is a mitogen-activated protein kinase kinasekinase that has been shown to cause neuroinflammation, but its mechanism of action has
been unclear. We generated conditional knockout mice that lack ASK1 in immune cells
or glial cells to assess the cell-type-specific roles of ASK1 in experimental autoimmune
encephalomyelitis (EAE), a model of multiple sclerosis (MS). We found that ASK1 isrequired in microglia and astrocytes to cause and maintain neuroinflammation by aproinflammatory feedback loop between these two cell types. Disruption of this feedback
loop by suppression of glial ASK1 may be a novel and effective approach for reducing
neuroinflammation.
We have also been examining the role of DOCK-D family proteins in neuroinflammation.
DOCK proteins are atypical guanine nucleotide exchange factors, and we found that
deficiencies in DOCK10 reduced neuroinflammation in EAE. Thus, inhibition of DOCK10 may
be useful for treatment of diseases such as MS and optic neuritis.
The Rho-ROCK pathway regulates actin cytoskeleton and dynamics, and we have recently
reported that application of the Rho-ROCK inhibitor ripasudil eyedrops promoted optic
nerve regeneration and neuroprotection by suppressing phosphorylation of CRMP2 andcofilin, two proteins involved in the Rho-ROCK pathway.

Selected Publications
Nishijima E, Honda S, Kitamura Y, Namekata K, Kimura A, Guo X, Azuchi Y, Harada C,

Brahma MM, Takahashi K, Namekata K, Harada T, Goshima Y, Ohshima T (2022) “Genetic

Murakami A, Matsuda A, Nakano T, Parada LF, Harada T (2023) “Vision protection andinhibition of collapsin response mediator protein-2 phosphorylation ameliorates retinal

robust axon regeneration in glaucoma models by membrane-associated Trk receptors."

ganglion cell death in normal-tension glaucoma models.” Genes to Cells 27(8), 526-536.

Molecular Therapy 31(3), 810-824.

environment on the degeneration of retinal ganglion cells in glutamate/aspartate

Namekata K, Harada T, Nakazawa T (2023) “Changes in glial cells and neurotrophic

transporter deficient mice, a mouse model of normal tension glaucoma.” Biochemistry

factors due to rotenone-induced oxidative stress in Nrf2 knockout mice.” Experimental

and Biophysics Reports 29, 101197.

Eye Research 226, 109314.

Sano H, Namekata K, Niki M, Semba K, Murao F, Harada T, Mitamura Y (2022) “Ocular

Shinozaki Y, Leung A, Namekata K, Saitoh S, Nguyen HB, Takeda A, Danjo Y, Morizawa

expression of cyclin-dependent kinase 5 in patients with proliferative diabetic

Y, Shigetomi E, Sano F, Yoshioka N, Takebayashi H, Ohno N, Segawa T, Miyake K,

retinopathy.” Journal of Diabetes Investigation 13(4), 628-637.

Kashiwagi K, Harada T, Ohnuma S, Koizumi S (2022) "Astrocytic dysfunction induced by
ABCA1 deficiency causes optic neuropathy.” Science Advances 8(44), eabq1081.
Guo X, Kimura A, Namekata K, Harada C, Arai N, Takeda K, Ichijo H, Harada T (2022) “ASK1
signaling regulates phase-specific glial interactions during neuroinflammation.” PNAS
119(6), e2103812119.

   46

Ohashi T, Namekata K, Guo X, Kimura A, Harada C, Harada T (2022) “Effects of lighting

Inoue-Yanagimachi M, Himori N, Uchida K, Tawarayama H, Sato K, Yamamoto M,

Diseases & Infection / PROJECT

Project Leader

Kazunori SANGO

After graduation from Yokohama
City University School of
Medicine in 1988, Kazunori
Sango worked at Yokohama City
University Hospital as a physician
and saw many patients sufferingfrom diabetic neuropathy andother complications. Inspiredby that experience, he started
to study the pathogenesisof diabetic neuropathy at
Department of Physiology,
Yokohama City University as a
graduate student. He received
Ph.D in 1992, and continued towork on pathogenic mechanismsof diabetic neuropathy andother neurodegenerative
disorders at National Institutesof He a l th, U S A ( 1 9 9 3 - 1 9 9 6) ,National Institute of Health andNutrition, Japan (1996-1999),
Tokyo Metropolitan Institute of
Neuroscience (1999-2011), andTokyo Metropolitan Institute ofMedical Science (2011-). He has
been the leader of the Diabetic
Neuropathy Project since2015, and his current interest istherapeutic approaches focusing
on the cross-talks among thepathogenic factors of diabetic
neuropathy, in particular,
collateral glycolysis pathways,
glycation and oxidative stress.

Diabetic
Neuropathy
Laboratory HP: https://www.igakuken.or.jp/diabetic/

Staff
Researchers
Mari SUZUKI
Hideji YAKO
Naoko NIIMI
Shizuka TAKAKU
Research Assistants
Kumi SUMIDA

Visiting Scientists
Koichi KATO
Tatsufumi MURAKAMI
Junji YAMAUCHI
Hitoshi KAWANO
Ken MURAMATSU
Keiichiro MATOBA
Tomoyo AKAMINE
Tomoko ISHIBASHI
Ryosuke SHINOUCHI

Students
Masaki OBA
Nozomi SAKATA
Yuki TAKEZAWA

Research Summary
One of the most common complications of Diabetes Mellitus,
and its symptoms such as pain and numbness can be the cause
of insomnia and depression. When allowed to progress to moreadvanced disease stages, peripheral neuropathy can result
in serious consequences such as lower limb amputation andlethal arrhythmia. In addition, recent studies have indicated that
diabetes is a major risk factor for cognitive disorders such as

Alzheimer’s disease.
The goals of our project are as follows:
1. Establishing effective pathogenesis-based treatments fordiabetic peripheral neuropathy.
2. Elucidating mechanistic links between metabolic dysfunction
and neurodegenerative diseases.

Project1:
Therapeutic Approaches to Diabetic Peripheral Neuropathy
Using diabetic model animals and culture systems of adult rodent dorsal root
ganglion (DRG) neurons and immortalized Schwann cells, we seek to establish
effective pathogenesis-based treatments for peripheral neuropathy.

Project2:
Mechanistic link between Metabolic dysfunction and Neurodegenerative Diseases
By using a Drosophila model, we aim to understand the molecular mechanismb y w h i c h me t a b o l i c c o n di t i o n s i n fl ue n c e mi sfo l di n g p r o t e i n - i nd u c ed
neurodegeneration.

Selected Publications
Nagai Y, et al. (2022) Rho-associated, coiled-coil-containing protein kinase 1 regulates

Akamine T, et al. (2020) Glycolaldehyde induces sensory neuron death throughdevelopment of diabetic kidney disease via modulation of fatty acid metabolism. Kidney

activation of the c-Jun N-terminal kinase and p-38 MAP kinase pathways. Histochem.

Int. 102:536-545.

Cell Biol. 153:111-119.

Yako H, et al. (2021) Role of pyruvate in maintaining cell viability and energy production

Lee JS, et al. (2019) Arylsulfatase A, a genetic modifier of Parkinson's disease, is an αunder high-glucose conditions. Sci. Rep. 11:18910.

-synuclein chaperone. Brain 142:2845-2859.

Takaku S, et al. (2021) Exendin-4 promotes Schwann cell survival/migration and*Nakamura S, *Oba M, et al. (2019) Suppression of autophagic activity by Rubicon is amyelination in vitro. Int. J. Mol. Sci. 22:2971.

signature of aging. Nat. Commun. 10:847. (*co-first authors)

Mizukami H, et al. (2020) Role of glucosamine in development of diabetic neuropathy

Takaku S, et al. (2018) Establishment of a myelinating co-culture system with a motor

independent of aldose reductase pathway. Brain Commun. 2:fcaa168.

neuron-like cell line NSC-34 and an adult rat Schwann cell line IFRS1. Histochem. Cell
Biol. 149:537-543.

47   

PROJECT / Diseases & Infection

Project Leader

Yuichiro MIYAOKA

Yuichiro Miyaoka has been
the leader of the Regenerative
Medicine Project since 2016.
He received his Ph.D. from theInstitute of Molecular and Cellular
Biosciences, the University ofTokyo under the supervision of
Dr. Atsushi Miyajima in 2009. After
receiving his Ph.D., he worked asa staff scientist in the Dr. Atsushi
Miyajima’s lab from 2009 to 2011.
Then, he did his postdoctoral
training in the Bruce Conklin’s
lab at Gladstone Institutes,
USA from 2011 to 2015, where
he developed the first digital
PCR-based method to detect
genome editing outcomes. He
applied this method to isolate
genome-edited cells without
antibiotic selection. His current
interest is to apply genome
editing in human iPS (induced
pluripotent stem) cells to curegenetic disorders by diseasemodeling, cell transplantation
therapy, and direct genetic
manipulation in patients’ cells. For
these therapeutic applications,genome editing should be
precise. Therefore, he also aims
to improve the accuracy andpredictability of genome editing.

Regenerative
Medicine
Laboratory HP: https://www.igakuken-regmed.com/home

Staff
Researchers
Tomoko KATO-INUI
Gou TAKAHASHI

Students
Ittetsu NAKAJIMA
Terumi ONO
Anri SAITOH
Minato MAEDA

Lanyu HUANG
Kayoko SHINOZAKI
Kanata IMAMURA
Yuga YASUDA

Research Summary
Genome editing technology allows us to rewrite the genetic
information in virtually any species and any cell type including
human cells. Our focus is on human iPS cells, a type of
pluripotent stem cell that can be generated from patients’ cells
by introduction of specific transcription factors, and differentiatedinto other cell types. Our goal is to use genome editing in iPS
cells to both model human diseases, and develop new therapies.
To achieve this goal, we are addressing the following challenges.

1) To establish isogenic disease models for cardiomyopathy,
hepatic disease, and neuronal disease to study theirpathogenesis.
2) T o develop therapeutic strategies by transplantation ofgenetically engineered iPS cells to cure genetic disorders.
3) To establish a way to directly manipulate genetic informationin patients’ cells.
4) To improve the accuracy and predictability of genome editing.

Our goal and approaches: By introducing or correcting pathogenic mutations in iPS cells,
we can establish isogenic disease models to study molecular pathogenic mechanisms.
We are modeling cardiomyopathy, hepatic disease, and neuronal disease. Geneticallyengineered iPS cells can also be used for transplantation therapies. We can potentiallycorrect mutations in iPS cells derived from patients, or even engineer the cells to express
therapeutic molecules. We are targeting metabolic diseases by cell transplantation
therapies. Because human iPS cells maintain the normal human genomic information,
genome editing in human iPS cells can be used as a model to develop a way to directly
manipulate genetic information in patients’ cells. We are also trying to improve theaccuracy and predictability of genome editing technology.

Selected Publications
Takahashi G, et al. (2022) “Genome editing is induced in a binary manner in single humanKato-Inui T, et al. (2018) “Clustered regularly interspaced short palindromic repeats

cells.” iScience. 25:105619.

(CRISPR)/CRISPR-associated protein 9 with improved proof-reading enhances*Song D, *Takahashi G, et al. (2022) “Retinoids rescue ceruloplasmin secretion andhomology-directed repair.” Nucleic Acids Res. 46: 4677-4688.

alleviate oxidative stress in Wilson’s disease-specific hepatocytes.” Hum. Mol. Genet.

Miyaoka Y, et al. (2018) “Detection and Quantification of HDR and NHEJ Induced by

31:3652-3671.

Genome Editing at Endogenous Gene Loci Using Droplet Digital PCR.” Methods Mol.

*Fenix AM, *Miyaoka Y, et al. (2021) “Gain-of-function cardiomyopathic mutations in

Biol. 1768: 349-362.

RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within

Miyaoka Y, et al. (2016) “Systematic quantification of HDR and NHEJ reveals effects ofprocessing bodies.” Nat Commun. 12:6324.

locus, nuclease, and cell type on genome-editing.” Sci. Rep. 6: 23549.
Miyaoka Y, et al. (2014) “Isolation of single-base genome-edited human iPS cells without   48

antibiotic selection.” Nat. Methods 11: 291-293.

Diseases & Infection / PROJECT

Project Leader

Hidetaka TANNO

Hidetaka Tanno has been theleader of the Cancer Immunology
Project since 2021. He obtained
his Ph.D. in 2013 from the Tokyo
Institute of Technology where
he studied ubiquitin-dependent
protein degradation under thesupervision of Prof. Masayuki
Komada. After graduating, heworked as a postdoctoral fellow
and focused on the developmentof new technologies in
immunology under thesupervision of Prof. George
Georgiou at The University ofTexas at Austin. During this time,
he developed a facile singlecell sequencing technology thatcan determine T cell receptor(TCR) and antibody sequencesat the repertoire level. At TMIMS,
he is using this technology to1) elucidate TCR repertoires incancer patients and 2) develop
new cancer therapeutics.

CancerImmunology
Laboratory HP: https://www.igakuken.or.jp/cancer_immunology/

Staff
Researchers
Mayumi SAEKI
Kazuhisa AOKI

Research Assistants
Noriko KITAMURA
Yuri TANNO

Research Summary
T cells play a critical role in adaptive immunity. They express
an enormous repertoire of TCRs on their surfaces. Using these
TCRs, T cells recognize antigen-HLA complexes presented bypathogenic cells and eliminate them. Therefore, elucidating theinteractions between TCRs and antigen-HLA complexes will be
useful for developing new therapeutics and preventive vaccines.
For example, cancer-specific TCRs have shown promising results
in recent clinical trials. However, it is still difficult to find useful
antigen-specific TCRs. In our project, we are developing newtechnology that can identify TCR-antigen-HLA interactions in ahigh-throughput manner. By employing this technology, we arecomprehensively analyzing cancer patients’ TCR-antigen-HLA
repertoires to discover cancer-specific TCRs that can be used for
T cell therapies. We will also apply this technology to elucidate
the mechanisms of virus infections and autoimmune diseases.

T cells recognize antigen-HLA complexes

There are diverse TCRs in human bodies including cancer-specific TCRs and virus-specific TCRs.

presented by pathogenic cells using TCRs.

Characterizing antigen-specificities of TCRs is necessary for engineered T cell therapy as well as vaccine
development. However, it has been difficult to determine the antigen-specificities of TCRs. We aredeveloping new technologies to identify TCR and antigen-HLA interactions at the repertoire level.

Selected Publications
M Kuraoka et al. (2022) “Infant Antibody Repertoires during the First Two Years of

CH Lee et al. (2017) “IgG Fc domains that bind C1q but not effector Fcγ receptors

Influenza Vaccination” mBio.

delineate the importance of complement-mediated effector functions.” Nature

J Li et al. (2021) “Molecular Level Characterization of Circulating Aquaporin-4 Antibodies

Immunology.

in Neuromyelitis Optica Spectrum Disorder” Neurology Neuroimmunology&Neuroinflam

JR McDaniel et al. (2016) “Ultra-high-throughput sequencing of the immune receptor

mation.

repertoire from millions of lymphocytes.” Nature protocols.

H Tanno et al. (2020) “A Facile Technology for the High Throughput Sequencing of the

B Wang et al. (2016) “Discovery of high affinity anti-ricin antibodies by B cell receptor

Paired VH:VL and TCRβ:TCRα Repertoires.” Science Advances.

sequencing and by yeast display of combinatorial VH: VL libraries from immunized

H Tanno et al. (2020) “Determinants governing T cell receptor α/β-chain pairing inanimals.” mAbs.

repertoire formation of identical twins” PNAS.

49   

ResearchCenters

Research Center / Genome & Medical Sciences

Vice Director

Hideya KAWAJI

Hideya Kawaji has been thevice director of Center for
Genome & Medical Sciences
since 2020. He received Ph.D
from the Graduate School ofEngineering Science, Osaka
University in 2003. He started his
research in information science,development of a method to
explore conserved sequence
domain in uncharacterized aminoacid sequences. He then moved
to RIKEN to study transcriptome
and its regulation throughtranscription starting site (TSS)
profiles at base-pair levels, with
development of computationaland experimental methodologies.
After working as researcher, unit
leader, coordinator at RIKEN
and visiting associate professor
at Yokohama City University, hemoved to the current position.
His current interest is the logic
of gene regulation encoded in
the human genome sequences,
impacting our health anddiseases.

Genome &MedicalSciences
https://www.igakuken.or.jp/genome-center/

Staff
Director
Hisao MASAI
Senior Researcher
Keisuke OBOKI

Researcher
Nobumasa WATANABE
Naoko YOSHIZAWA
Toyoaki NATSUME
Yuichiro HARA
Saki SAITO
Nilmini HETTIARACHCHI

Research Summary
Our body consists of around thirty-seven trillion cells, each ofthem carries almost identical genetic information composedof three billion base-pairs. Meanwhile, individual cells expressa unique subset of genes, not all, and the expressed ones
comprise the molecular basis within (or outside sometimes) thecells. Our genomes carry the structural information specifying
both expressed molecules (genes), and the regulatory signals
orchestrating molecules to be present in the cells (regulatory
elements).

genome-wide experiments with large-scale computing. We will
also seek the opportunities of collaborations with other researchgroups in TMIMS to accelerate medical science in individual
fields, and with hospitals to understand diseases and to develop
new diagnostics and therapeutic tools.

Given that such protein coding sequences occupy only 1 ~ 2%of the genome, identification of functional regions within theremaining 98 ~ 99% is crucial in understanding human biology
as well as in interpretation of human diseases. Through a unique
RNA profiling technology, called CAGE (Cap Analysis Of Gene
Expression), that determines frequency of transcription initiation
at the base-pair resolution across the genome, we discovered aseries of regulatory regions, called promoters and enhancers, 10fold or more than the protein coding genes. It indicates presenceof still uncovered regulatory regions, and raises a challenge
to assess their contribution to the expression of genes. We aregoing to tackle these challenges by combining high-throughput

Selected Publications
Jayakumar V, et al. (2021) “Chromosomal-scale de novo genome assemblies of

Yoshida, E., et al. (2017) “Promoter-level transcriptome in primary esions of endometrial

Cynomolgus Macaque and Common Marmoset.” Sci Data. 8(1):159.

cancer identified biomarkers associated with ymph node metastasis.” Sci. Rep. 7(1):14160

Abugessaisa I, et al. (2021) “FANTOM enters 20th year: expansion of transcriptomic

Takamochi,K., et al. (2016) “Novel biomarkers that assist in accurateÝiscrimination ofatlases and functional annotation of non-coding RNAs.” Nucleic Acids Res.

squamous cell carcinoma from adenocarcinoma of the ung.”BMC Cancer 16(1): 760.

49(D1):D892-D898.

   52

Kawaji, H., et al. (2014) “Comparison of CAGE and RNA-seq ranscriptome profiling using

Ito Y, et al. (2021) “Nanopore sequencing reveals TACC2 locus complexity and diversity

clonally amplified and single-molecule ext-generation sequencing.”Genome Res.

of isoforms transcribed from an intronic promoter.” Sci Rep. 11(1):9355.

24(4):708–717.

Hirabayashi S, et al. (2019) “NET-CAGE characterizes the dynamics and topology of

Forrest, A.R.R., Kawaji,H., et al. (2014) “A promoter-level mammalianÞxpression atlas.”human transcribed cis-regulatory elements.” Nat Genet. 51(9):1369-1379.

Nature, 507(7493):462–70.

Social Science & Medicine / Research Center

Director Unit Leader

Atsushi NISHIDA

Atsushi Nishida has been theleader of the Unit for Mental
Health Promotion and the
director of the Research Center
for Social Science and Medicine
since 2020. Previously he worked
as a research scientist from 2008
to 2010 at the Tokyo Instituteof Psychiatry, and from 2010 to2014 at the Tokyo Metropolitan
Institute of Medical Science.
He was a visiting scientist at
University College of London
MRC Unit in Lifelong Health &Aging from 2012 to 2014, andthe project leader for the Mental
Health Promotion Project at theTokyo Metropolitan Institute ofMedical Science from 2015 to2020.

MentalHealthPromotion
https://www.igakuken.or.jp/english/r-center_en/rc-social_e/unit-mhp.htmll

Staff
Researchers
Syudo YAMASAKI
Mitsuhiro MIYASHITA
Kaori BABA

Junko NIIMURA
Kaori ENDO
Satoshi YAMAGUCHI

Research Summary
Mental health is important for one’s quality of life (QOL). Duringadolescence, healthy physical and mental development lays
the foundations for a better QOL and is also an integral part ofa flourishing society. On the other end of the spectrum, since
we live in a hyper-aging society where it is not uncommon forpeople to live to 100, more and more old people are experiencedementia. It is therefore necessary to create a social system thatallows people with dementia to live happy healthy lives.
The Unit for Mental Health Promotion examines mental healthissues that have a direct impact on the health and livelihoodsof Tokyo residents, from childhood mental health issues todementias affecting the elderly. We use research methods fromboth social and clinical epidemiology, including cohort studies
and randomized controlled trials, to better understand thesocietal and environmental conditions which will enrich people's
mental well-being from birth to old age. In this way, we aim tocontribute towards building a society which promotes the mental
health needs of the people of Tokyo and elsewhere.

Teen Cohort is a project that

We are promoting the participation

We have developed a care program

scientifically examines how toof people with mental illnesses

to support people with dementia,

support young people as they facein creating a platform for them toand are verifying the effectivenessthe future and grow into adults.

participate in research and serviceof the program and promoting it toplanning.

all municipalities in Tokyo.

Selected Publications
Nishida A,et al (2022) ” Comparison of lithium levels between suicide and non-suicide

Nakanishi M, Nishida A, et al (2022) “Neighborhood Social Cohesion and Dementia-

fatalities:cross-sectional study.” Translational Psychiatry,

Related Stigma Among Mothers of Adolescents in the Pre- and Current COVID-19

Stanyon D, Nishida A , et al (2022) “Auditory hallucinations and self-injurious behavior
in general population adolescents: modeling within-person effects in the Tokyo Teen

Period: An Observational Study Using Population-Based Cohort Data.” Journal of
Alzheimer's Disease, 88 (2) 493–502.

Cohort.” Schizophrenia Bulletin,
Nishida A, et al (2022) “Ethnoracial variation in risk for psychotic experiences.
Schizophrenia Bulletin, “53   Social Science & Medicine / Research Center

Unit Leader

Yuki NAKAYAMA

Yuki Nakayama received her
Ph.D. from Tokyo University of
Health and Science in 2006 afterworking as a nurse. She joined
the Tokyo Metropolitan Instituteof Medical Science in 2007. ​She has been a project leader for
intractable disease care nursing
since 2015.
Her specialty is the nursing
research for intractable diseases,
and she has carried out researchon the support of the social
participation of ventilator
users and research activities
contributing to respiratory
management and improvementof QOL.

Intractable
DiseaseNursingCare
https://nambyocare.jp/
https://www.igakuken.or.jp/english/r-center_en/rc-social_e/unit-idnc.html

Staff
Researchers
Michiko HARAGUCHI
Chiharu MATSUDA
Akiko OGURA
Yumi ITAGAKI

Research Assistants
Saori KAWAMURA
Sachiko KOBAYASHI
Kaoru MORISHITA
Kayoko SHIMIZU
Kazuyo SHIMIZU
Yoshie SANO
Chizu MAEDA

Research Summary
Since the establishment of our laboratory, we have pursued
methods for alleviating sufferings related to human dignity suchas difficulty in breathing, inability to swallow food, and inability
to communicate, as well as support systems for living a safe
and secure life for recuperation in familiar areas, targeting ALS(amyotrophic lateral sclerosis) patients who are said to havethe most severe medical and disability needs. This unit aims tocontribute to the improvement of the quality of life of people
living with incurable diseases by presenting a home care supportmodel in Japan, which is facing a super-aging society, while
inheriting this tradition.
Our Research Objectives are,
To promote the practical application of new communications
support technologies and create a support system that can beused when needed
To improve nursing care that will lead to the dignity and life
maintenance of patients with ALS and other severe disabilities

To promote the enhancement of a safe care environment andsupport system through the promotion of home care safety andhealth activities for patients with intractable diseases

Selected Publications
Nakayama Y, Shimizu T*, Matsuda C ,Haraguch M et al. (2022) “Body Weight Gain is

Matsuda C, Shimizu T, Nakayama Y, Haraguchi M. (2019) “Cough peak flow decline rate

Associated with the Disease Stage in Advanced Amyotrophic Lateral Sclerosis withpredicts survival in patients with amyotorophic lateral sclerosis” Muscle & Nerve. 59(2)Tracheostomy and Invasive Ventilation, Metabolites.” Metabolites 2022, Volume 12, Issue

168-173.

2, 191
CazzolliPA, BrooksRB, Nakayama Y et al.(2020) “The Oral Secretion Scale and Prognostic
Factors for Survival in Subjects. With Amyotrophic Lateral Sclerosis.” Respiratory Care.
65(8)1063-107
Nakayama Y, Shimizu T, Matsuda C, Haraguchi M, et al. (2019) “Body weight variation
predicts disease progression after invasive ventilation in amyotrophic lateral sclerosis.”
Scientific Reports volume 9, s41598-019-48831-9
Shimizu T, Nakayama Y, Matsuda C, Haraguchi M, et al. (2019) “Prognostic significance ofbody weight variation after diagnosis in ALS: a single-centre prospective cohort study.”
Journal of Neurology .266(6), 1412–1420   54

Shimizu T, Nakayama Y, et al. (2018) “Sensory cortex hyperexcitability predicts shortsurvival in amyotrophic lateral sclerosis.” Neurology 1 ;90(18): e1578-e1587.
Nakayama Y, Shimizu T,Matsuda C, et al. (2018) “Non-Motor Manifestations in ALS
Patients with Tracheostomy and invasive ventilation.” Muscle and Nerve. 57(5):735-741.
Nakayama Y, Shimizu T, Matsuda C, et al. (2016) “Predictors of impaired communicationin amyotrophic lateral sclerosis patients with tracheostomy invasive ventilation.”
Amyotroph Lateral Scler Frontotemporal Degener. 17(1-2):38-46

ResearchSupports

Research Support

Basic
Technology
Research
Laboratory HP: https://www.igakuken.or.jp/english/center/basic/basictech.html

Director

Minoru SAITOEThe Basic Technology Research Center provides resources to assist scientists
to conduct their research efficiently. We provide state-of-the-art technologies
required for biomedical and life science research and maintain various facilities
used by researchers.

1. The Animal Research Division maintains our animal facilities
and provides care and welfare for the animals used in research.
This division assists researchers in generating transgenic andknock-out animals and maintains sperm and eggs of various
mutant animal lines.
2. The Advanced Technical Support Department provides stateof-the-art technology for our scientists including facilities forprotein analyses, FACS, microarrays, confocal and electron
microscopy, histology and other technologies.
3. The Information Support Department consists of the library,
the information technology section, the media technology
laboratory, and the public relations office. It assists researchers
in searching for references and information, deals with themedia and public relations, and provides support for our
computer systems.
4. The Authorized and General Core Facility Department consistsof the radioisotope laboratory, the hazardous chemical control
room, and the general common facility. It provides researcherswith various special and common facilities and maintains safety
standards for accident-free daily operation of the institute.

   56

Research Support

Technology
Licensing
OfficeTLO HP: https://www.igakuken.or.jp/english/center/tlo/tlo.html

General Manager

Kazumasa AOKIWho we are

What we do• T he Technology Licensing Office (TLO) facilitates theconversion of scientific discoveries to innovative technologies
with the ultimate goal of improving public health and welfare.

• We manage intellectual properties from our institute including
patents, copyrights and materials in order to develop them forcommercialization.

• W e evaluate basic research findings (seeds) as intellectual• T o promote technology transfer, we introduce seeds andproperty assets, and license promising candidates to industries
for development as medicines, diagnostics, medical devices,
foods, cosmetics and research tools.

intellectual properties with potential commercial value topharmaceutical, medical device, and startup companies.

Researchers

Discoveries

Evaluation

TLO

Related Contracts••

Management ofIntellectual Properties•

Marketing•

Licensingor Collaboration

Industries•

License Agreements
MTAs(Material
Transfer
Agreements)
CDAs(Conﬁdential
Disclosure
Agreements)
Collaboration
Agreements
Consulting
Agreements• We attend business meetings such as the BIO international
convention in the US, BIO-EUROPE, and BioJapan, to develop
Public Private Partnership opportunities between industries andour institute.
• W e support collaborative research projects with industries
by arranging Joint Research Agreements, Material Transfer
Agreements (MTA), and other contracts to protect and develop
a wide range of research discoveries.

Commercialization

57   

Research Support

Medical Research
Cooperation
Laboratory HP: https://www.igakuken.or.jp/english/center/tr/tr.html

Staff
Kimi UEDA

Chikako ISHIDA

Hiroko KOUSAKA

Strengthening Medical Research by Bringing Research Institutes and Hospitals
Together - From bench to bed and back again -Director

Takayuki HARADA

We facilitate collaboration between basic scientists at research institutes andmedical doctors at hospitals. We have a supporting budget of 500,000 yen forcollaborative clinical studies with medical doctors at Tokyo Metropolitan Hospitals.
We manage ethical issues related to human specimens and we provide specialized
support for bringing knowledge and findings from basic scientific research todevelopment of new therapy in humans.

Conference with researchers and medical

A young scientist discussing with medical

doctors

Conference with researchers and medical
doctors in conference

Neuropathology
Laboratory HP: https://pathologycenter.jp/english/en_index.html
Translational Research using human materials and Management of
Database for Essential Brain Anatomy & Neuropathology

Staff
Masato HASEGAWA Rika KOJIMA
Kenichi OSHIMA
Nobuko UEKI
Erika SEKI
Tomoko YAGIThe Laboratory of Neuropathology conducts neuropathological research using
specimens of human origin. The laboratory features fixed asset management
and research use of approximately 5,000 human neuropathology specimens
and samples, one of the largest in Japan and abroad; research and educationaluse of a neuropathology image database using virtual slides from a highprecision digital scanner; and dissemination and use of specialized techniques
by faculty members specializing in neuropathology.
   58

Tsunemi YAMANISHI
Keiko AKAMATSU

We are one of the rare laboratories preparing large brain sections in Japan.
The large brain section allows us to detect the distribution patterns oflesions in brain diseases.

Public Relations
andOther Activities

TMIMS Programs
Public Lectures

TMIMS Seminar Series on "Aging and Health"

Each year we present 8 pubic lectures to inform the public of our research
progress and enlighten people on various medical issues pertinent to theirhealth and welfare. In 2022, we conducted 2 on-line lectures and 6 hybrid
lectures. Lecture topics included hay fever, dementia, cancer treatment, sleep
disorders and circadian clock.

In 2022, we have initiated a special TMiMS seminar series,“Aging and Health”, where we have invited prominentscientists in the field, to have lectures of the forefront
research on aging as well as on how to promote healthy life.
We had 3 lectures in 2022, and 8 more lectures are being
planned in 2023.

Latest trends in the therapies and reserch for Japanese ceder pollinosis
Development of curative therapy for pollinosis by SLIT.................. Minoru GOTOH (Nippon Medical School)
SLIT: How does it work?
.................. Mayumi SAEKI (TMIMS, The Laboratory of Allergy and Immunology)
Heart-reaching Care for people with dementia: psychosocial approach and family support.................. Miharu NAKANISHI (Tohoku University)
Molecular biology of cancer and current trends for novel therapies
Molecular biology of cancer and current trends for novel therapies.................. Takuro NAKAMURA (Tokyo Medical University)

TMIMS Seminar Series on "Aging and Health"Can we overcome aging?
.................. M akoto NAKANISHI(The University of Tokyo)
Mental health and aging.................. Masanari ITOKAWA (TMIMS) xercise that activates brain-how to move your body for healthyE
aging.................. K ando KOBAYASHI(The University of Tokyo)

Stem cell-mediated novel cancer immunotherapy and drug development.................. Takahiko HARA (TMIMS, Stem Cell Project)
Revolution in treatment of spinal muscular atrophy led by mass screening
Novel therapies for spinal muscular atrophy facilitated by mass screening.
.................. Kayoko SAITO (Tokyo Women's Medical University)
Mass screening of newborns for treatment of spinal muscular atrophy.................. Tomoko MIZUNO (Tokyo Medical and Dental University)
Vaccine development: past, present and future
Science of vaccine: from molecules to ethics.................. Ken ISHII (The University of Tokyo)
Vaccine development with vaccinia virus vectors: classic approach with a new touch.................. Fumihiko YASUI (TMIMS, Viral Infection Control Project)
Sleepy?
Sleep apnea and Sleepiness.................. Hideaki NAKAYAMA (Tokyo Medical University)
Evaluating excessuve daytime sleepiness and “inemuri-byo”(narcolepsy).................. Makoto HONDA (TMIMS, Sleep Disorders Project)
Circadian rhythm: body clock for healthy life
Circadian rhythm: body clock for healthy life.................. Yoshitaka FUKADA (The University of Tokyo)
How do living species count 24 hours?
.................. Hikaru YOSHITANE (TMIMS, Circadian Clock Project)
What is BPSD (Behavioral and Psychological Symptoms of Dementia)?
.................. Shunichiro SHINAGAWA (The Jikei University School of Medicine)

Science café
In the past eleven years we have had 41 special
science presentations geared toward the generalpublic. These “science cafes” provide people of allages with the opportunities to learn, experience, andenjoy science first hand in a casual setting. In 2022,
we had three on-line science cafes on human bodyoperation and genomes. The participants enjoyed
our on-line quizzes in these events.

   60

Battle between cancer and immune system in our body...................................................Hidetaka TANNO(TMIMS, Cancer Immunology project)
Let us zoom in cells: Proteins in action...................................................Yasushi SAEKI(TMIMS, Protein Metabolism project)
Let us zoom in cells: Injured genomes...................................................Hiroyuki SASANUMA(TMIMS, Genome Dynamics project)Institutional seminars (Igakuken Seminars)
We have institutional seminars on a regular basis. In 2022, despite the continued coronavirus pandemic,
we had 25 seminars (9 on zoom and 16 on hybrid format) by both domestic and foreign scientists(seven scientists based outside the country) including those from Saint John's College Oxford andJohns Hopkins Universities in USA. We were particularly excited to be able to invite world-prominentscientists to the Igakuken Seminars by taking advantage of the use of the on-line presentation.

Creation of multicellular network by designing cell-to-cell communication................Satoshi TODA (Kanazawa University)

X-chromosome Inactivation, Color Vision, and the Female Advantage................Jeremy NATHANS (Johns Hopkins Medical School)

Challenge for sustainable medicare................Taro UENO (SUSMED, Inc)

Plasticity of neuronal excitability and synaptic transmission in Drosophila:functional implications from milliseconds to lifetime................Atsushi UEDA (University of Iowa)

The genome of the Mus musculus, the wild house mouse................Hitoshi SUZUKI (Hokkaido University)
Business strategy of Brain Therapeutics, Inc.: development of drug delivery
system to brain................Fumikazu WANIBUCHI (Braizon Therapeutics, Inc.)................Masahiro Ohtsu (Braizon Therapeutics, Inc.)The Scent of food; physiological roles................Motoko OHATA (Nihon University)
Evolution of human brain function: Probing primate brain by non-invasive
brain Electroencephalogram................Kosuke ITOH (Niigata University)

Brain dysplasia: insight from studies on the human brain evolution................Takashi NANBA (University of Helsinki)Life and GTP, a new frontier................Atsuro SASAKI (University of Cincinnati)“Red Queen Hypothesis” in human-specific immune receptors................Kohyuki HIRAYASU (Kanazawa University)
Novel functions of glutamic acid in brain................Miho TERUNUMA (Niigata University)
Perception, memory and evolution of life, a view from multi time scale theory................Yasushi HIRAI (Fukuoka University)

Detection and analysis of the sound-evoked nanoscale vibrations incochlear sensory epithelium by an advanced interferometer................Takeru OTA (Osaka University)

Social inequalities in adolescent mental health in London: the Resilience,
Ethnicity, and AdolesCent Mental Health (REACH) cohorts.
................Gemma Knowles(King’s College London)

Understanding the mechanism of chromosome segregation: lessons from diversity................Bungo AKIYOSHI (University of Oxford)

Strategic plans of PhoenixBio................Takashi SHIMADA (PhoenixBio Co., Ltd.)

Neurons of development in the adult brain................Zoltán Molnár (Saint John's College Oxford)

Successfully completing the final stretch – termination of DNA replicationin the bacterial chromosome................Christian RUNDOLPH (Brunel University London)

Transient neurons and transient networks in the developing cerebral cortex................Heiko LUHMANN (University Medical Center Mainz)
Behavioral addiction to internet games.................Ichiro SORA (Kobe University)

Circadian RNA Biology – How do RNAs regulate circadian rhythms?
................Shihoko KOJIMA (Virginia Tech)

Regenerative medicine of retina by using ES/iPS-derived retinal tissue / cells................Michiko MANDAI (Kobe City Eye Hospital)

TMIMS International Symposium

Joint programs with universities

After more than three years of interval, we were able to have23rd TMIMS International Symposium “New Frontiers in Ubiquitin
Proteasome System” in 2022 (December 6) at the auditorium. We
had 7 invited foreign speakers, 4 domestic invited speakers, and 7
speakers from our institute. It was a very active meeting with a lot of
discussion and scientific interactions.

Many scientists at TMIMS have joint appointments as visiting
professors or lecturers at various
universities. In 2022, we held our annual “open institute” events forprospective graduate students
on-line with close to 100 attendants. We currently have 108 students
from affiliated universities andother schools, who conduct their research here.

We give lectures to high-school and university students who visit our
institute and we also send staffs to visit schools and deliver lectures.
This year, we gave face-to-face lectures at Toyama high school
delivered by Makoto HONDA and Taku MIYAGAWA and at
Gakugeidai-Fuzoku high school by Sho SUGAWARA. We also gave
on-line seminars for the undergraduate students of Department of
Biosciences, College of Humanities and Sciences, Nihon University.

都医学研で修士・博士研究
やってみる？

オンライン開催(Zoom)
参加方法の詳細、プログラム、資料、
アーカイブ配信については下記の
URLをご確認ください。

理学、工学、農学、医学、歯学、薬学、獣医学、保健学、心 https://www.igakuken.or.jp/public/event/220423.html
理学等の学部・学科等に在学する大学生や関連する専門
学校生、大学院生及び既に医師として従事している方

都医学研
連携大学院
説明会

開催日
2022.

4.23
5.14

(オンライン

土 研究室訪問あり)
土 (一部録画)

13:00〜16:00

6月上旬～6月30日頃を予定

5月29日(日)13:00～

23rd TMIMS International Symposium

New Frontiers
in Ubiquitin
Proteasome System
Date

2022.12.6 Tue

Venue

TMIMS Auditorium

Speakers

Alessio Ciulli (University of Dundee, UK)
Daniel Finley (Harvard Medical School, USA)
Claudio Joazeiro (ZMBH, Germany)
Hiroyuki Kawahara (Tokyo Metropolitan
University)【所長挨拶・研究所紹介】
正井 久雄 所長
【連携教官による講演】
脳機能再建プロジェクト
西村 幸男 プロジェクトリーダー【連携大学院生からの話】【研究室紹介】【質疑応答】【オンライン 研究室訪問(4/23のみ)】David Komander (WEHI, Australia)
Eri Sakata (Göttingen University, Germany)
Kylie Walters (NCI/NIH, USA)
Hsueh-Chi Sherry Yen (Academia Sinica,
Taiwan, China)
andTMIMS Researchers and Friends

Organized by

Yasushi Saeki (TMIMS)

東京都医学総合研究所では、医学に関する様々な研究に興味・意欲のある方をお待ちしています。

Contact

お問合せ 事務局 研究推進課 企画係 連携大学院担当（公財）東京都医学総合研究所 第 23 回都医学研国際シンポジウム事務局

TEL：03-5316-3107 E-mail：daigakuin@igakuken.or.jp〒156-8506 東京都世田谷区上北沢 2-1-6

e-mail symp@igakuken.or.jp

Support for students and young scientists
Research Associate Fellowships
We provide graduate students who conduct their masters/Ph.D.
research at TMIMS with research associate fellowships that allow
them to concentrate on their studies and research.

Travel support for young scientists attending
international meetings
We provide students and young scientists at TMIMS with travel
fellowships to attend international meetings where they can present
their results and meet other students and scientists in their fields.

61   Access Map

AIRPORT to INSTITUTE●From Kamikitazawa Station to Institute

Walk (approx. 10 min From South entrance of Station).
●From Hachimanyama Station to InstituteTOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE

2-1-6 Kamikitazawa, Setagaya-ku,
Tokyo, 156-8506, Japan
Tel:+81-3-5316-3100 Fax:+81-3-5316-3150

https://www.igakuken.or.jp/english/
As of March 1, 2023