Annual
Reports 2021

Contents
02 Message from the Chairperson
03 Our Mission
04 Message from the Director: TMIMS2021
06 Special Team for COVID-19 Countermeasures: Message from Team Director
08 Organizational Chart • Our People at a Glance
09 Meet our scientists!
16

Our Goal

18

Research Activities

19

Department of Basic Medical Sciences

20 Genome Dynamics Project............................................................................................................. Hisao MASAI
21

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

22

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

23

Ubiquitin Project...................................................................................................................................... Noriyuki MATSUDA

24

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

25

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

26

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

27

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 ARAI
39

Affective Disorders Research Project..................................................................................... Yoshitaka TATEBAYASHI

40 Sleep Disorders Project..................................................................................................................... Makoto HONDA
41

Addictive Substance Project......................................................................................................... Kazutaka IKEDA

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
50 Laboratory of Allergy and Immunology............................................................................... Takachika HIROI
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.
Between 2020 and 2021, the highly contagious COVID-19 disease
spread throughout the world causing unprecedented damage
at all levels of society. Combatting this disease is a top priority.
At TMIMS, we swiftly set up a “Coronavirus Countermeasures
Special Team” two years ago and in cooperation with theTokyo Metropolitan Government, we have been making every
effort to develop effective strategies to eliminate this disease.
Particularly, epidemiological studies such as monitoring of theresident population in the major downtown areas of Tokyo havecontributed greatly to the Tokyo Metropolitan Government's
countermeasures against COVID-19 disease, and we have also
started our own highly original vaccine development researchagainst SARS-CoV-2. However, unfortunately, the pandemic
is still ongoing and TMIMS will need to continue fundamental
research in order to develop effective countermeasures tocombat the disease in 2022.
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 interest and   2

Keiji TANAKA
knowledge of science and research. Accordingly, TMIMS aims tobe acclaimed both academically and culturally for the knowledge
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 topdown, exit-oriented, applied research (of immediate use), andbottom-up, future-oriented fundamental research (seemingly
not of immediate use). Balancing these two research strategies,
TMIMS endeavors to operate in a flexible manner in order toachieve additive and synergistic effects. Top-down and bottomup research strategies are not incompatible, but can work in acooperative and harmonious manner. Throughout the history ofscience, we can find numerous examples of seemingly uselessresearch suddenly becoming useful, resulting in great service tosociety.
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 fromour director: TMIMS 2021
in the battle against diseases. SARS-CoV-2 vaccines weredeveloped less than one year after its outbreak and saved
millions of lives. No one, even the most knowledgeablevirologists or immunologists, could have predicted these eventsat the beginning of 2020. One of the technologies used for thisventure, mRNA vaccines, opened up a new avenue for thegeneration of drugs utilizing RNA to target various diseases
including cancers.
Novel Prize 2021: The 2021 Nobel Prize in Physiology or Medicine
was awarded to Professors David Julius and Ardem Patapoutian
for their discoveries of the sensing mechanisms for temperatureand touch. The first breakthrough came from the search fora gene that can react to capsaicin from chili peppers. Julius
and colleagues identified TRPV1 and subsequently identified
other family members that sense the temperature. Patapoutainand colleagues identified receptors for mechanical stimuli byscreening for genes responsible for responses when cells are
poked with a micropipette. Piezo1, named after the Greek word
for pressure, and its relative Piezo2 were shown to be ion channels
directly activated by the exertion of pressure on cell membranes.
Piezo2 turned out to be a key protein for proprioception (sensingof body position and motion). Understanding how cells senseheat, cold and mechanical stimuli helped us understand how weperceive and adapt to the world around us.

Director

Hisao Masai
2021 forced us once again to fight against COVID-19. Morethan two years since the start of the outbreak, the world is still
suffering from the pandemic. Although the infection rate inJapan fortunately decreased in early September 2021, we still
do not know the exact cause. Now a new strain is threatening
the world and it is hard to predict how the situation will change.
Indeed, we have experienced a sharp rise of cases in early 2022.
As a medical institute whose goal is to improve the health andmedical care of people, we have been helping the public byproviding the latest information related to infections, diseases
and vaccinations. In addition, we are testing our own novel,
potent vaccines against SARS-CoV-2, and are further pursuing
strategies for the rapid development of vaccines for new viruses
that will almost certainly appear in the future (see page 6 fordetails on our activities for combating COVID-19).
Science in 2021
Power of Science: In 2021, we witnessed the power of science   4

A basic principle of life: Professor Tuneko Okazaki was awarded
the Order of Culture in 2021 for her ground-breaking discoveries
in the basic mechanism of DNA replication. Professor Okazaki, in
collaboration with her husband, Professor Reiji Okazaki, solved
one of the great mysteries of DNA replication, namely, how canboth strands of anti-parallel DNA be replicated by a polymerasethat can synthesize DNA in only one direction? While replicationof one strand, the leading strand, could be understood easily,
unwinding of the opposite strand, the lagging strand, should be“backwards” with respect to polymerase synthesis. In a relentlessseries of experiments, Tuneko and Reiji demonstrated that thelagging strand is replicated by the polymerase as short pieces
of DNA synthesized in the opposite direction as unwinding.
These short DNA fragments are then joined together to generatemature daughter DNA strands. This discontinuous mode of
DNA replication was shown to be a universal principle of DNA
replication, and the short pieces of DNA were named “Okazaki
fragments”. Reiji, who had been exposed to radiation in the
Hiroshima atomic bomb, died of leukemia at the age of 44 in 1975.
Under the difficult conditions facing female scientists nearly 50
years ago in Japan, Tuneko, a mother of two, led the laboratory
and continued her studies on mechanisms of discontinuous
DNA replication, and is now regarded as a pioneering role model
for female Japanese scientists. The discovery of discontinuous
DNA replication and initiation of DNA synthesis by RNA primerswas a foundation for the development of DNA amplification
by PCR (polymerization chain reaction), and has had profound
implications in other important biological issues such as evolution
and left-right asymmetry. The discovery of Okazaki fragments
demonstrates how uncovering a basic principles of life can leadto development of truly useful new technologies and bring new
insights into many other general biological problems.
Life science and global warming: In 2021, scientists were pushed
more than ever into global issues. Rising global temperatures
are causing devastating weather changes throughout the world,
including the recent giant tornados that wiped out large areas incentral USA. The concentration of greenhouse gases continues
to increase. CO2 emissions have now returned to pre-pandemic
levels and will continue to increase. The sea-level will continue
to rise (3.7mm/ year) and world-wide efforts to adapt will be
important. Scientists from all fields need to unite to develop
efficient strategies to curb global warning, and help affected
people adapt to changes.
What can we, as life science researchers, do to mitigate thesecrises? Life science research can contribute to green recovery
in many different manners. For example, cattle farming is
responsible for the release of a large amount of methane, andtherefore, new cattle feed that produces less methane as well as
plant-based meat alternatives will provide promising solutions
to the problem. To achieve net zero emissions of CO2, utilizationof algae or bacteria to remove carbon from the atmosphereand the oceans could be excellent tools to develop industrial
systems for removal of greenhouse gases. Cutting-edge sciencein combination with rapid industrialization made accelerated
production of vaccines possible during this pandemic. Similar
efforts by life science researchers will undoubtedly be crucial
for restoring the planetary health and achieving sustainable
development goals.
TMIMS 2021
Our institute is now in its second decade after its establishment
in 2011. Our research projects have 5 year terms, and we are now
in the second year of the 4th term. This year, we started two new
projects, the Circadian Clock Project led by Dr. Hikari Yoshitane
and the Cancer Immunology Project led by Dr. Hidetaka
Tanno, and we now have 23 projects and two laboratories in
4 departments. We also have two research centers that werestarted in 2020.
In 2021 we had in-house scientific gatherings featuring
presentations from select scientists and graduate students fromthe institute. Although we could not invite any foreign scientists
to physically visit the institute this year, we had various renowned
foreign scientists present institutional seminars online (see page60-61). We also continued our outreach activities including eightlectures for the public and three Science cafés, which wereconducted online.
Our clinical collaborations with hospitals are critical forconnecting our basic research findings to the developmentof novel therapies and treatments. We started two newcollaborations with hospitals in 2021, and now have a total of 7
ongoing collaborative projects.
Also in 2021, we reached agreements with Ochanomizu Women’s
University and the National Center of Neurology and Psychiatry(NCNP) for mutual visits, collaborations, sharing of resources andequipment and education of students and young researchers.

This will increase the research and educational opportunities
available to students and enhance scientific and educational
collaborations between the institutions.
Research achievements in 2021
Despite the difficulties imposed by the pandemic, many new
findings were reported last year from the institute. I’ve listed someof the most notable below. The Dementia Research Project led by
Dr. Masato Hasegawa clarified the relationship between structuralfeatures of protein precipitates responsible for dementia/
neurodegenerative diseases and their pathological consequences.
In a collaboration between TMiMS, NCNP, Brain banks from Japanand overseas, and the MRC (Medical Research Council, United
Kingdom), research groups elucidated the structures of protein
fibers of tau, α-synuclein, and TDP-43 isolated from diseased
brains. These findings were reported in four Nature articles during
the past two years. Dr. Shinobu Hirai from the Neural Development
Project found that high-sucrose diets impaired glucose uptake
from blood vessels and augmented brain dysfunctions related
to psychosis in mice. These results were reported in Science
Advances. Dr. Daisuke Yamane from the Viral Infection Control
Project discovered that iron-dependent fatty acid desaturationinduces cell death through ferroptosis and inhibits hepatitis
C virus replication (reported in Cell Chemical Biology). Kotaro
Nakamura, a graduate student in the Stroke Renaissance Project(led by Dr. Takashi Shichida), identified DJ-1 as a DAMP (DamageAssociated Molecular Patterns) which induces inflammation in
the ischemic brain, and showed it can be a therapeutic target forischemic brain. This was reported in PLoS Biol. Dr. Yukiko Yoshida
form the Ubiquitin Project and her collaborators elucidated themechanism of pathogenesis of NGLY1-deficient syndrome, arare human disease. The group showed that accumulation ofaberrantly ubiquitinated glycosylated polypeptides in NGLY1deficient cells causes proteasome dysfunction, leading to diseasephenotypes (reported in PNAS). Dr. Guo from the Sleep Project (ledby Dr. Takayuki Harada) used conditional knockout mice to showthat a feedback loop between microglia and astrocytes involving
the ASK1 protein causes and maintains neuroinflammation (PNAS
in press).
Outlook for 2022
Synergy, sharing and internationalization will continue to be
the keys for the future development of the institute. TMiMS
was originally formed by combining three previously separate
research institutes, and during the past ten years the threedifferent cultures of medical science have been merging
constructively. Now we need to harness the growing seeds fromthis merger into larger trees with ripe fruit. From our strong basic
research activities, we aim to identify the hidden principles of life.
This will help us understand diseases pathogenesis, which will
ultimately lead to the development of truly useful technologies
and therapies. In 2022, we will continue to strive for new
discoveries that will contribute to the health and welfare of the
public.
With the uncertainties of the COVID-19 pandemic in 2022, we willcontinue our efforts in novel vaccine development and conduct
research to better understand the nature of the virus and its
epidemiology in order to develop new drugs and treatments. We
will also contribute to policy-making by the Tokyo Metropolitan
Government through providing social dynamics data.
I strongly hope that 2022 will bring us back to a more normal life
where we do not need to worry about the numbers of the cases
everyday, where we can travel freely, have in person discussions,and even have parties!
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 a pointof 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 the beginning ofBacteriology in 19 centuries. Tokugawa shogunate had prohibitedlearning European science and philosophy to maintain feudalism
for over 200 years. Science and medicine have been imported
from European countries because the shogunate changed the   6prohibition policy since the mid 18 centuries. A lot of samurai
became "Samurai-Scientists" by learning Dutch medicine. Their
first lime-lighted fine performance was emergency medicalcare for the patients of the cholera pandemic at the end of 19
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. Hisao Masai
has been analyzing SARS-CoV-2 genomes by collaboratingwith the National Institute of Genetics to recognize variations
including novel ones. 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. S anada T, Honda T, Yasui Fumihiko, 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 (in press)
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:

Director General:

Keiji TANAKA
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(Shinichi NISHIMURA)

Our People at a Glance

February 1, 2022   8

Meet ourscientists!

Meet our scientists!
The hepatitis C virus (HCV) is a leading cause of chronic liver disease. While effective treatments exist, up to 5% of infected
people do not respond to these treatments, resulting in tens of millions of people worldwide suffering from incurable
liver disease. Daisuke Yamane, a senior scientist in the Department of Diseases and Infection at TMIMS, has been studying
HCV. He previously discovered a curious phenomenon. HCV viral replication is strongly inhibited by lipid peroxidation, themetabolic oxidative degradation of cellular lipids (Nature Medicine 2014 20:927-35.). In his current work, entitled “FADS2dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus
replication,” (Cell Chemical Biology 2021 S2451-9456(21)00362-7. ) he uncovered metabolic pathways that inhibit viral
replication and identified therapeutic targets for novel HCV treatments.

Daisuke
YAMANEHow did you become interested in science?
When I was in elementary school, I learned about viruses
such as Ebola and HIV. I became very curious and wanted
to know what they look like and how they behave in ourbodies to cause disease. That was my first motivation to
become a scientist and study viruses.
What do you enjoy most about research?
I enjoy discovery. I can come up with a hypothesis andI can test it. If the hypothesis turns out to be true, theHepatitis C virus induces remodeling of host membranes into specialized structures enriched in lipids (Red, Caveolin-2) to create
viral replication factories (Green, hepatitis C virus antigen). Blue, Nucleus.
   10findings lead to a new paper that can sometimes influencepeople. I just really want to know what the truth is.
How did you become interested in hepatitis C?
I went to veterinary school and first studied a bovine virus,
bovine viral diarrhea virus, which is closely related tohepatitis C virus (HCV). From there, I became interested
in HCV. However, HCV clinical isolates are very difficult togrow in cell culture. Their replication efficiency is very low.
I tried to improve culture conditions and found that HCV
is very sensitive to exogenous polyunsaturated fatty acids(PUFAs). When I added PUFAs to cell culture, it induced
lipid peroxidation and this impaired viral replication. I
also did the reverse experiment where I inhibited lipid
peroxidation using vitamin E, a physiological lipid-soluble
antioxidant. When I treated cells with vitamin E, I foundthat lipid peroxidation was reduced and viral replication
was dramatically increased ~10 fold. From these results,
I realized that cellular lipid peroxidation rates strongly
influence HCV replication.
What is lipid peroxidation?
Lipid peroxidation is a process that degrades fatty acids,
specifically PUFAs. PUFAs have multiple double bondsthat can be attacked by free radicals. This process of
attacking double bonds is amplified by chain reactions
between multiple double bonds, leading to degradationof PUFAs. Lipid peroxidation is always going on at low
levels in cells. Membranes have to turn over. However,when we age, lipid peroxidation increases and, in thiscase, it may be part of a pathological condition.
Why does replication of hepatitis C virus virus depend on
the lipid metabolism state?
There are lipid peroxidation-resistant variants of HCV.
These variants replicate efficiently in vitro, but in vivo,

these viruses replicate too fast and are easily recognizedby the immune system and eliminated. In contrast,
peroxidation-sensitive viruses are more stealthy. They
can infect liver cells and hide from the immune system,
replicating only when the lipid peroxidation is low.
They replicate gradually and slowly hijack the host cell.
In fact, HCV can also induce lipid peroxidation itself.
When it replicates to a threshold level, it induces lipid
peroxidation which downregulates its own replicationin an autoregulatory circuit. Thus, we consider that thesensitivity to lipid peroxidation may provide an advantage
for the virus to persist in the host.
What is a significant finding in your Cell Chemical Biology
paper?
Our paper has multiple significant findings. One is that ferroptosis
inducers inhibit HCV replication. Ferroptosis is a type of cell
death induced by iron. Iron acts as an oxidant and attacks the
double bonds present in PUFAs to induce lipid peroxidation. We
found that low concentrations of ferroptosis inducers that didn’t
kill cells were sufficient to inhibit HCV replication. Furthermore,
we found that ferroptosis inducers combined with direct antiviral
agents that target the viral protease, a component of the viral
replication machinery, exerted synergistic effects and eliminatedthe virus much more efficiently. Overall, we determined how
hepatocytes restrict HCV replication through lipid metabolism
and discovered how we may manipulate this pathway to improvetherapy for hepatitis C patients.

What are your future plans?
HCV clinical isolates are still difficult to grow in culture so weare trying to develop a better cell culture system that is moresimilar to liver tissue in order to grow the virus more efficiently.
We believe this will be important for antiviral testing and vaccine
development. Despite the availability of oral drugs, HCV is still amajor worldwide health concern and we think the developmentof vaccines is necessary for the complete elimination of HCV.
Interviewed by Jun Horiuchi

Daisuke Yamane (the first from the right on the the front row) and his former colleagues at the University of North Carolina at Chapel Hill in Prof. Stan Lemon's laboratory.

11   

Meet our scientists!
Psychiatric disorders are complex diseases that have a combination of genetic and environmental causes. While various
genes that affect diseases such as schizophrenia and bipolar disorders have been identified, environmental contributions
and the interactions between genetic and environmental effects that cause these diseases have not been as wellstudied. Shinobu Hirai, a senior scientist in the department of Psychiatry and Behavioral Sciences has been studying how a
combination of genetic and environmental influences can result in metabolic changes that cause psychiatric effects. Herlatest results were published in a paper entitled, “High-sucrose diets contribute to brain angiopathy with impaired glucose
uptake and psychosis-related higher brain dysfunction in mice” (Sci Adv. 7, eabl6077(2021)). We spoke to her about her
work.

Shinobu
HIRAI
How did you first become interested in science?
My parents were both scientists. My father was a syntheticorganic chemist, and my mother was a microbiologicalengineering chemist. When I was a child, they kept asking
me questions about the world to stimulate my curiosity
and increase my love for learning. In school, I loved mybiology classes so I entered this field.
How did you become interested in diet and psychiatricdiseases?
When I was in college, I lived on my own, and started
eating a lot of sweets instead of eating a balanced diet.
Because of this, I got sick, and my doctor told me to stopeating so poorly. After that I started eating more carefully
and I became interested in how diets affect our mental
health.

   12What was the start of your research for your Science
Advances paper?
Patients with psychiatric diseases such as schizophrenia
or bipolar disease eat much more sugar than healthy
individuals, and those who eat more sugar tend to havemore severe symptoms. Schizophrenia and bipolar
disorders are caused by a complex interaction of genetic
and environmental risk factors. From these observations,
I decided to examine the connection between excess
sugar consumption and psychosis-related behaviors.
Is there a connection between excess sugar consumption
and psychiatric illnesses?
Yes! In my experiments, I used two different types of
mice, one was a normal control and one expressed
reduced amounts of GLO1, a protein that protects cells
from oxidative damage. Reductions of GLO1 have been
associated with schizophrenia. I fed these mice two typesof diets. One was a high sucrose diet, and the other wasa control starch-based diet. So, altogether I had a totalof four different experimental conditions. When I lookedat various behaviors, I found that GLO1 mutant mice fed
high sucrose diets exhibited behaviors associated withschizophrenia and bipolar disorders, while mice in thethree other conditions didn’t. Human schizophrenia andbipolar patients have changes in dopamine signaling in
the brain and alterations in activity of certain neurons,
called parvalbumin-positive neurons, and I found that
GLO1 mutant mice fed high sucrose had similar changes.
From these results, I concluded that a high sucrose dietcan work in combination with a genetic predisposition tocause psychiatric disease.
How do high sucrose diets contribute to psychiatricdiseases?
Both excess sucrose consumption and decreased GLO1
activity increase oxidative damage in our bodies. So, I
thought that a combination of sucrose and decreased
GLO1 could have additive or synergistic effects, and alarge increase in oxidative stress could cause psychiatricillness. Indeed, I found a strong increase in oxidative
damage, in blood vessels in brains of GLO1 mutant
mice fed high sucrose. I also found that these mice had

increased neuroinflammation and increased activation of
immune cells and glia. These changes were accompanied
by damage to the brain vasculature and decreased brain
glucose. Interestingly, I found similar damage to the brain
vasculature in the postmortem brains of schizophrenic
and biopolar disorder patients. Overall, I think thatoxidative damage to blood vessels decreases the amountof glucose transported to the brain. This leads to changes
in brain activity and psychiatric illness.
How can we prevent damage to the brain vasculature?
Interestingly, I found that chronic low dose aspirin
treatment prevents damage to the brain vasculature andrescues glucose uptake to the brain. It also decreased
psychiatric behaviors. Aspirin suppresses inflammationand smoothens blood flow. I think it may also decrease
accumulation of AGEs (Advanced Glycation End products).
What are your future plans?
Recently I’ve been studying how glucose is transported
into the brain and I’ve obtained some fascinating results
about a possible role for astrocytes. I’m really excited topursue this research!
Interviewed by Jun Horiuchi

13   Meet our scientists!
Inflammation can be a protective response by the body to harmful stimuli such as pathogens, tissue damage, and irritants,
but it can also have adverse effects. For example, inflammation can increase the severity of various diseases, including
cerebral pathologies. Koutarou Nakamura, a graduate student in the Stroke Renaissance Project, studies the inflammatory
response to ischemic stroke and identified a novel signaling pathway through which strokes induce inflammation. He
further found that inhibition of this pathway decreases the damage caused by strokes. We spoke to him about his recent
results, published in a paper entitled, “Extracellular DJ-1 induces sterile inflammation in the ischemic brain,” PLOS Biology|
https://doi.org/10.1371/journal.pbio.3000939 May 20, 2021.

Koutarou
NAKAMURA

How did you become interested in science?
When I was in high school, I had an excellent biology
teacher who was so enthusiastic about biology that
he taught us using university textbooks even though
we were still in high school. In his class, I became
impressed with the beauty of the immune system - how
T cells, B cells, neutrophils, and many other cell types
communicate with each other in a coordinated manner
to protect our bodies from pathogens. When I was athird-year undergraduate student in university, I met Dr.
Shichita, who was starting a new research lab at TMIMS.
He invited me to join as a Master’s student. It was a great
opportunity for me. Dr. Shichita’s goal was to combine thefields of immunology and neurosciences, and I was very
excited to join his group to study inflammatory responses
in ischemic strokes.
   14

What are ischemic strokes?
Ischemic stroke is a brain disease where clogged bloodvessels decrease cerebral blood flow. This blockage
causes brain cells, including neurons, to die, leading
to impaired brain functions, such as loss of movement
or loss of verbal functions. One of the consequencesof ischemic strokes is severe inflammation and thisdrastically worsens disease pathology. However, thedetailed mechanisms that cause inflammation have notbeen sufficiently clarified, and we wanted to tackle thisproblem.

Why does inflammation occur?
Inflammation has both protective and harmful effects on
the body. When pathogens or viruses invade our bodies,pattern recognition receptors on natural immune cells
recognize these invaders. This activates natural immune
cells and causes them to produce inflammatory cytokines,
which protect our bodies and recruit other immune cells
to the area of invasion, triggering further inflammatory
immune responses. However, this inflammation also leads
to severe brain edema and brain deficits after strokes. So,
while inflammation has protective roles, it can also harm
our bodies and worsen the pathology of diseases such as
strokes.
Could you explain your results published in PLOS biology?
Even though we know that inflammation worsens thepathology of strokes, the detailed mechanisms causing
inflammation were unclear. We wanted to reveal thesemechanisms. In this paper, I found a molecule called DJ1, which triggers severe inflammation after strokes andworsens stroke pathology.
Interestingly, we’ve found that DJ-1 has two opposing
functions: one is cytoprotective, and the other is
inflammatogenic. When DJ-1 is inside cells, it functions
as a potent antioxidant that protects cells from oxidative
stress and reactive oxygen species (ROSs). In ischemic
strokes, reduced blood flow increases oxidative stressin neurons, leading to the production of harmful ROSs. In
intact neurons, DJ-1 would catabolize ROSs, protecting
cells from oxidative damage. However, we found thatin more severe strokes where neurons have died fromnecrosis, DJ-1 is released into the extracellular spaceand functions as a signaling molecule to infiltrating
immune cells to induce inflammation. Those endogenous
molecules which induce inflammation are called DAMPs(Damage Associated Molecular Patterns) and we showedthat DJ-1 is one of the major DAMP in ischemic stroke.
When we knocked out DJ-1 in mice, we observedthat inflammation after ischemic stroke was strongly
suppressed. However, DJ-1 knock-out mice had similar
damage after stroke compared to normal mice. We thinkthat is because DJ-1 has both protective and deleterious
effects and knocking out DJ-1 removes both effects.
So, we next developed neutralizing antibodies to DJ-1,
which would mainly affect the harmful extracellular DJ1. When we injected these antibodies into mice, we foundthat they reduced inflammation and greatly improved
pathology after ischemic stroke.
What are your plans for the future?
I think that DJ-1 is a very promising therapeutic target fordeveloping more effective treatments for stroke and otherdiseases associated with inflammation. Also, althoughDJ-1 antibodies are expensive, they could be further
developed for treatments of inflammation. For myself,
I’m currently interested in studying endogenous repair
mechanisms in the brain. Usually the brain isn’t thought ofas a very repair-friendly organ, but I’ve recently obtainedsome interesting results that I’m eager to pursue further.
Interviewed by Jun Horiuchi

Schematic model of the roles of DJ-1 in the ischemic brain
injury. DAMP, damage-associated molecular pattern; ROS,
reactive oxygen species.

15   Ou r Go a l   16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.

17   Research
Activities

Rad5 1 foci induced by ionizing irradiation in human B cells

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 primordial mode of DNA
replication, and the roles of
unusual nucleic acid structures,
including G-quadruplexes and
RNA-DNA hybrids in shaping
chromosomes, copying andreading genetic information, andcausing detrimental diseases.

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

Staff
Senior Researcher
Hiroyuki SASANUMA
Researchers
Zhiying YOU
Kenji MORIYAMA
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
Shunsuke KOBAYASHI
Hao-Wen HSIAO
Kaho TAKASAWA
Naoya INOUE
Trinh Thi To NGO
Shoha KINOSHITA
Ayaka ONUKI

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) How do cells respond to replication stress, and how are these
responses coordinated with other cellular stress response
pathways?
4) What are the roles of replication factors in the development of
individual organs and tissues? How do defects in these factors
cause human diseases?

5) H ow have replication systems evolved and diversified in
response to changing environments?
6) What are the roles of replication and checkpoint factors indevelopmental processes?

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 generateconfined, but dynamic and interactive chromatin compartments.

Selected Publications
Yoshizawa-Sugata, et al. (2021) “Loss of full-length DNA replication regulator Rif1 in
two-cell embryos is associated with zygotic transcriptional activation.” J Biol Chem,
297,101367.
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
Kobayashi S, et al. (2019) “Both a unique motif at the C terminus and N-terminal HEAT
repeat contribute to G4 binding and origin regulation by Rif1 protein.” Mol Cell. Biol. 39(4).

   20

pii: e00364-18
You Z and Masai H (2017) “Potent DNA strand annealing activity associated with mouse
Mcm2~7 heterohexamer complex.” Nucleic Acids Res. 45, 6495-6506.
Yang C-C, et al. (2016) “Claspin recruits Cdc7 kinase for initiation of DNA replication inhuman cells.” Nature Communications 7:12135.
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
Kunie MATSUOKA
Shumpei YASUDA
Yuta SEKI

Students
Ikuo MIURA
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
Seki et al. (2021) “Myosin VI haploinsufficiency reduced hearing ability in mice.”

Seki Y, et al. (2017) “A novel splice site mutation of myosin VI in mice leads to

Neuroscience. 478:100-111.

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

Yasuda SP et al. (2020) “c.753A>G genome editing of a Cdh23

ahl

allele delays age-related

ear hair cells.” PLoS One 12, e0183477.

hearing loss and degeneration of cochlear hair cells in C57BL/6J mice.” Hear. Res. 389:

Miyasaka Y, et al. (2016) “Heterozygous mutation of Ush1g/Sans in mice causes early-

107926.

onset progressive hearing loss, which is recovered by reconstituting the strain-specificMatsuoka 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 the
inner ear.” Sci. Rep. 9:5285.
Yasuda SP, et al. (2018) “Effects of genetic background on susceptibility and themutation 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.

acceleration of hearing loss in mice.” An Excursus into Hearing Loss 3–23.

21   

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.”   22

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

USA, 111: E5527-5536.

Basic Medical Sciences / PROJECT

Project Leader

Noriyuki MATSUDANoriyuki Matsuda has been theleader of the Ubiquitin Projectsince 2015. He received his
Ph.D in 2001 from the Universityof Tokyo Graduate School of
Science for identification of themembrane-bound RING fingertype ubiquitin ligase, Rma1/Rnf5,
from H. Sapiens and A. thaliana(Matsuda, J. Cell. Sci. 2001). He
then worked as a postdoctoral
fellow studying mechanisms
and functions of ubiquitylation
under the supervision of Dr.
Keiji Tanaka at the Tokyo
Metropolitan Institute of Medical
Science. His current interests
are to understand how ubiquitin
is conjugated on damaged
mitochondria, how thesemitochondria are degraded in a
mitochondria-specific autophagic
process known as mitophagy,
and how mitophagy prevents
detrimental diseases such as
Parkinson’s disease.

Ubiquitin
Laboratory HP: https://www.igakuken.or.jp/english/project/detail/ubiquitin.html

Staff
Researchers
Yukiko YOSHIDA
Koji YAMANO
Fumika KOYANO

Postdoctoral fellows
Waka KOJIMA

Students
Anni HUO
Chisato UDAGAWA
Rhota HAYASHIDA

Research Summary
Parkinson's disease (PD) is a common movement disordercharacterized by loss of dopaminergic neurons. The majority of
PD cases are sporadic, however, the discovery of genes linked tohereditary forms has provided important insights into molecularmechanisms associated with PD pathology. For example,
functional analysis of recessive familial PD-related genes has
identified a link between PD and mitochondrial quality control.
However, the molecular mechanisms underlying this relationshiphave been obscure.
We focused on two genes associated with hereditary recessive
PD, PINK1 and PARKIN. PINK1 encodes a Ser/Thr kinase and
PARKIN encodes a RING-IBR protein. We found that whenthe mitochondrial membrane potential decreases, a sign ofmitochondrial damage, PINK1 phosphorylates ubiquitin at Ser65.
Phosphorylated ubiquitin activates the ubiquitin ligase (E3)function of Parkin (Koyano Nature 2014). Moreover, ubiquitin
chains phosphorylated by PINK1 function as Parkin receptors
and recruit Parkin to damaged mitochondria (Okatsu J.Cell.Biol .
2015). Consequently, the trio of PINK1, Parkin, and phosphoubiquitin induced rapid ubiquitination of mitochondrial outermembrane proteins. Since a bewildering array of substrates are
ubiquitinated by Parkin during this process, Parkin substratespecificity remained poorly understood. We found, using artificial
mitochondria-targeted proteins, that substrate specificity of

Parkin is not determined by specific amino acid sequences but
instead by mitochondrial localization (Koyano J.Biol .Chem . 2019).
Ubiquitin is well-known for directing proteins for degradation.
However, increasing evidence indicates that ubiquitination is
also involved in quality control of larger structures includingorganelles, by tagging and directing damaged organelles forautophagic degradation. We found that ubiquitin chains on
depolarized mitochondria are recognized by OPTN, an adaptor
protein that recruits ATG9, a downstream autophagic protein, todamaged mitochondria (Yamano J.Cell.Biol . 2020). Impairment of
this process prevents mitochondrial degradation and induces apredisposition to familial PD. Our work identifies a mechanism for
PD pathology.

Schematic model for how PINK1, Parkin, and ubiquitin cooperate in the
degradation of damaged mitochondria.

Selected Publications
Yoshida Y, et al.(2021) “Loss of peptide:N-glycanase causes proteasome dysfunction

Koyano F, et al.(2019) “Parkin recruitment to impaired mitochondria for nonselective

mediated by a sugar-recognizing ubiquitin ligase.” Proc. Natl. Acad. Sci. USA 118:

ubiquitylation is facilitated by MITOL.” J Biol Chem 294: 10300-10314.

e2102902118.
Kojima W, et al.(2021) “Mammalian BCAS3 and C16orf70 associate with the
autophagosome formation site in response to selective and non-selective autophagy.”
Autophagy 17: 2011-2036.

Koyano F, et al.(2019) “Parkin-mediated ubiquitylation redistributes MITOL/March5 frommitochondria to peroxisomes.” EMBO Rep. 20: e47728.
Yamano K, et al.(2018) “Endosomal Rab cycles regulate Parkin-mediated mitophagy.”
eLife 7: e31326

Yamano K, et al.(2020) “Critical role of mitochondrial ubiquitination and the OPTN-ATG9A
axis in mitophagy.” J. Cell Biology 219: e201912144.

23   

PROJECT / Basic Medical Sciences

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
Shoma YAMAGUCHI
Risa SAITO
Shiho SASAKI
Minako SHINGAI
Fumiya SEKI
Hikaru ANDO

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
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.”
Micromachines, 11: 305.
Nakajima M, et al. (2019) “In vitro differentiation of mouse T cell-derived hybrid cells
obtained through cell fusion with embryonic stem cells.” Biochem. Biophys. Res.
Commun. 513: 701-707.

   24

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.

Basic Medical Sciences / PROJECT

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
Akinori ENDO
Hikaru TSUCHIYA
Takuya TOMITA
Emeritus Researcher
Hiromichi YONEKAWA

Visiting Scientists
Fumiaki OHTAKE
Sayaka YASUDA
Supervisor
Keiji TANAKA

Research Assistants
Naoko ARAI
Sayaka ONO
Yasuko KAWASEHarumi SETO
Kyoko UEDA
Students
Miho SAKUMA

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.

25   

PROJECT / Basic Medical Sciences

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
Tomoko TANAKA
Research Assistants
Arisa KURABAYASHI

Visiting Scientist
Yoshitaka FUKADA
Miho YOSHIMURA

Students
Yasuko ABE
Yuta OTOBE
Satoshi KAWAKAMI
Shunsuke ITOTaiki MORIMURA

Research Summary<background>
Many organisms exhibit circadian rhythms, which are governedby a 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
Masuda et al., (2020) “Mutation of a PER2 phosphodegron perturbs the circadianTerajima et al., (2017) “ADARB1 catalyzes circadian A-to-I editing and regulates RNA

phosphoswitch.” Proc. Natl. Acad. Sci. USA, 117(20): 10888-10896.

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

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

Yoshitane et al., (2014) Molecular and Cellular Biology, 34(10): 1776-1787.

mRNA rhythms.” Communications Biology, 2: 300.
Imamura et al., (2018) “ASK family kinases mediate cellular stress and redox signaling tocircadian clock.” Proc. Natl. Acad. Sci. USA, 115(14): 3646-3651.

   26

Yoshitane et al., (2012) EMBO Reports, 13(5): 455-461.
Yoshitane et al., (2009) Molecular and Cellular Biology, 29(13): 3675-3686.

Basic Medical Sciences / PROJECT

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
Ikuo KAWASHIMA
Kiyoshi OGURA
Tetsuya HIRABAYASHI
Keisuke KOMATSUYANorihito KIKUCHI

Students
Mai KAWAGUCHI
Jun KANBE

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 from the nervous system, and in platelet cells from theblood.

signals through interactions with Lyn/Cbp proteins found inganglioside GD3-rich rafts of cerebellar granule cells. We further
found that the chemokine SDF-1α triggers the chemoattractionof cerebellar granule cells during cerebellar development.
SDF-1α stimulates GTPγS binding to Goα, and causes Goαtranslocation to lipid rafts, leading to growth cone collapse of
cerebellar granule cells.
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
αIIbβ3-myosin axis in sphingomyelin-rich membrane rafts that is
important in clot retraction.

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
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.(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.

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

Kasahara K, et al. (1997) “Association of src family tyrosine kinase Lyn with ganglioside

Blood 115, 1277-1279.

GD3 in rat brain. Possible regulation of Lyn by glycosphingolipid in caveolae-likeYuyama K, et al. (2007) “Translocation of activated heterotrimeric G protein Gαo todomains.” J.Biol.Chem. 272, 29947-29953.

27   Surface structures of the cross section of TDP-43 fibers isolated from brains of ALS
patients. Red, hydrophobic amino acids; blue, hydrophilic amino acids

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
Masami SUZUKAKE
Fuyuki KAMETANI
Ito KAWAKAMI

Postdoctoral fellows
Taeko KIMURA
Research Assistants
Reiko OOTANI

Students
Yuuya HANZAWA
Mina TAKASE
Aiko ISAMI

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 proteins prepared in these
diseases, immuno-histochemically, ultrastructurally, and biochemically 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 pathological tau and alpha-synuclein
filaments from brains of patients with corticobasal degeneration (CBD) and multiple
system atrophy. We further identified numerous post-translational modifications in thesefilamentous 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 toconvert endogenous soluble alpha--synuclein monomers into amyloid-like fibrils.

Selected Publications
Tarutani A, et al. (2021) “Human tauopathy-derived tau strains determine the substrates

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

recruited for templated amplification.” Brain. Sep 4;144(8):2333-2348.

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

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.
Shi Y, et al. (2021) “Structure-based classification of tauopathies.” Nature. Sep 29. Online
ahead of print. (Oct.14)
Zhang W, et al. (2020) “Novel tau filament fold in corticobasal degeneration.” Nature
Apr;580(7802):283-287.

   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
Postdoctoral fellows
Hiroshi KUROMI

Research Assistants
Saki KOMIYA
Takae HASEGAWA
Tomoko TAKAMISAWA

Students
Maximiliano
Martinez-Cordera

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: h ttps://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
Miki KANESHIGE
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 obtained his MD(1993) and PhD (2005) degrees
from Tokyo Medical and
Dental University and trainedin pediatric neurology at the
National Center of Neurology
and Psychiatry. He then studied
neuroimmunology at the National
Institute of Neuroscience with
Prof. Sachiko Miyake in 2010,and has been involved in Health
Labour Sciences Researchon virus-associated acuteencephalopathy since 2010. He
has been working at the Tokyo
Metropolitan Institute of Medical
Science since 2012. His current
interests include 1) mechanismsof virus-associated acuteencephalopathies including
febrile infection-related epilepsy
syndrome, 2) biomarkers forpediatric immune-mediatedneurological diseases, and 3)
generating an international
consensus on pediatricautoimmune neurologicaldiseases.

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

Staff
Researchers
Tadayuki SHIMADA
Hiroko SUGIURA
Kuniko KOHYAMA

Visiting scientists
Hiroko TADA
Ai HOSHINO
Misato TSUBOITomonori 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 childhood autoimmune andinflammatory neurological diseases (AINDs). These diseases area significant social burden because of poor prognosis and highmortality. We have created a multicenter registry of patients andsample repository for AINDs, based on nationwide collaborations,which we are using for cohort studies. We perform multi-omics
analyses of biomarkers including inflammatory mediators,
microRNAs, and metabolites. This multifaceted approach using
high-throughput methods enables us to explore novel moleculartargets associated with AINDs.
Recent studies have highlighted the importance of glial cells
in the pathogenesis of AINDs. We have developed transgenic
animal models to determine how glial cells contribute topathomechanisms of AINDs by regulating brain metabolism
and inflammation. These studies will help us develop novel
therapeutic strategies.

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 a CD4 T-cell mediated disease in which
autoreactive T cells are activated, proliferate, migrate to the 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 the periphery and the central
nervous system. Although the pathogenesis of virus-associated encephalopathy has
not been fully elucidated, pro-inflammatory cytokines and chemokines are highly
increased in biofluids, suggesting cytokine-mediated mechanisms.

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

Igarashi A, *et al. (2018) “Cytokine-induced differentiation of hematopoietic cells into

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

microglia-like cells in vitro.” Clin. Exp. Neuroimmunol. 9:139-149.

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

Saika R, et al. (2017) “MicroRNA-101a regulates microglial morphology and inflammation.”

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

J. Neuroinflammation 14:109

Mizuguchi M, et al. (2020) “Guidelines for the diagnosis and treatment of acute

Sakuma H, et al. (2015) “Intrathecal overproduction of proinflammatory cytokines

encephalopathy in childhood.” Brain Dev. 43:2-31.

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

Suzuki T, et al. (2020) “Extracellular ADP augments microglial inflammasome and NF-κB

Neurosurg. Psychiatr. 86:820-822

activation via the P2Y12 receptor.” Eur. J. Immunol. 50:205-219.

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
Keiko MORIYA-ITO

Research Assistants
Kumiko HIRAI
Aiko ODAJIMA
Yoshiko TAKAHSAHI
Ayako MORITA

Students
Hitomi ACHIWA
Kyosuke WADA
Xiang SONG
Mayu OZAKI
Yusuke SUGITA
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
Ohtaka-Maruyama C (2020) “Subplate neurons as an organizer of mammalian

Ohtaka-Maruyama C, et al. (2018) “Synaptic transmission from subplate neurons controls

neocortical development. ”Front. Neuroanat. 14, 8.

radial migration of neocortical neurons.” Science 360, 313-317

Nomura T, et al. (2020) “Changes in Wnt-dependent neuronal morphology underlie the

Ohtaka-Maruyama C, et al. (2013) “RP58 regulates the multipolar-bipolar transition of

anatomical diversification of neocortical homologs in amniotes.” Cell Reports, 31,107592.

newborn neurons in the developing cerebral cortex.” Cell Reports, 3, 458-471

Kamimura K et al. (2019) “The HSPG Glypican Regulates Experience-Dependent

Kamimura, K, et al. (2013) “Perlecan regulates bidirectional Wnt signaling at the

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

Drosophila neuromuscular junction.” J Cell Biol. 200, 219-233.

Reports, 28, 3144-3156.

35   Genome-wide association study (GWAS) on postherpetic neuralgia. Genetic
polymorphisms in the region of the ABCC4 gene that encodes ATP binding cassette
subfamily C member 4 are associated with postherpetic neuralgia.

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
Mitsuhiro MIYASHITA
Kazuya TORIUMI
Hiroaki ISHIDA

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

Students
Yasuhiro MIYANO
Koichi TABATA
Mai ASAKURA
Tianran WANG
Kyoka IINO
Mayuko MASADA
Azuna OZAWA
Chinatsu SUGIMURA
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
Miyashita M, et al. (2021) “Fingertip advanced glycation end products and psychotic

Toriumi K, et al. (2021) “Vitamin B6 deficiency hyperactivates the noradrenergic system,

symptoms among adolescents.” NPJ Schizophr. 7:37.

leading to social deficits and cognitive impairment.” Transl Psychiatry. 11: 262.

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

Koike S, et al. (2021) “Analysis of carbonyl proteins accumulated in the brain of mousein a schizophrenia model system causes mitochondrial dysfunction in the prefrontal

model for methylglyoxal detoxification deficits by feeding Glo1 knockout mice withcortex.”Redox Biology 45: 102057.

VB6-lacking diets.” Antioxidants. 10: 574.

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

Mizutani R, et al. (2021) “Structural diverseness of neurons between brain areas andnumber variable microRNAs in schizophrenia with enhanced glycation stress.” Transl

between cases.” Transl Psychiatry. 11: 49.

Psychiatry. 11:331.
Kobori A, et al. (2021) “Advanced glycation end products and cognitive impairment inschizophrenia.” PLoS One. 16: e0251283.

   38

Saiga R, et al. (2021) “Brain capillary structures of schizophrenia cases and controls showa correlation with their neuron structures.” Sci Rep. 11:11768

Psychiatry & Behavioral Sciences / PROJECT

Project Leader

Yoshitaka TATEBAYASHI

Yoshitaka Tatebayashi has
been the head of the Affective
Disorders Research Projectsince 2014. He obtained his MD
from Osaka University Schoolof Medicine in 1989 and worked
at Osaka University Hospitalfrom 1989 to 1990, the Graduate
School of Medicine at Osaka
University from 1990 to 1994, andthe Department of Neurology
at Nippon Life Hospital from1994 to 1996. He then worked
as a research scientist at theInstitute for Basic Research in
Developmental Disabilities from1996 to 2000, and at RIKEN Brain
Science Institute from 2000 to
2004. He was the director of theDepression Laboratory at theTokyo Institute of Psychiatry from2004 to 2011, and the directorof the Depression Laboratory at
TMIMS from 2011 to 2014.

Affective
Disorders
Research
Laboratory HP: https://www.igakuken.or.jp/affective/english/reserch-1.html

Staff
Researchers
Naomi KIKUCHI-NIHONMATSU
Yoshiki MATSUDA
Kazuhisa AOKITakiko SHINOZAKI
Nobuyuki OZAWA

Research Summary
Major depressive disorder (MDD) and bipolar disorder (BD),collectively known as affective disorders, are relapsing andremitting disorders of affect with nearly full recovery between
episodes. We use human postmortem brains and animal andcell culture models to identify the processes in which stress or
aging causes changes in the brain to induce these disorders.
An initial focus of our work was stress-induced or age-relatedchanges in cellular structure and lipid composition, particularly
in oligodendrocyte cells within the brain’s mood circuitry. We arealso interested in the biological relationship between affective
disorders and dementias such as Alzheimer’s disease.

Selected Publications

We recently established a novel rat social defeat stress (SDS)
model that develops prolonged MDD-like maladaptive social
avoidance and sleep abnormalities. These abnormalities wereassociated with changes in electroencephalography (EEG)
spectral powers, including reduced REM sleep theta power.
Chronic treatment with two different classes of antidepressants(ADs), imipramine and fluoxetine, as well as preventative use ofergothioneine, a metabolite of the gut bacterium Lactobacillus
reuteri, significantly ameliorated these behavioral, sleep, and EEG
abnormalities.
Interestingly, REM theta power was normalized by chronic
but not acute AD administration. We speculate that the
septohippocampal pathway, including the medial septum andhippocampus, may be partially or largely impaired by SDS,
resulting in both
emotional and/or
cognitive symptoms in
our model.
Inflammation may be
involved in this processsince ergothioneine has
a strong anti-oxidative
as well as antiinflammatory effects.

Matsuda Y, et al. (2020) “Ergothioneine, a metabolite of the gut bacterium Lactobacillus

Tatebayashi Y, et al. (2012) “Abnormal fatty acid composition in the frontopolar cortex ofreuteri, protects against stress-induced sleep disturbances.” Transl. Psychiatry 10:170.

patients with affective disorders.” Transl. Psychiatry 2:e204.

Bauer M, et al. (2014) “Relationship between sunlight and the age of onset of bipolar

Hayashi Y, et al. (2012) “Neuropathological similarities and differences between

disorder: an international multisite study.” J. Affect. Disord. 167:104-111.

schizophrenia and bipolar disorder: a flow cytometric postmortem brain study.” PLoS

Nihonmatsu-Kikuchi N, et al. (2013) “Depression and Alzheimer’s disease: novel

One 7: e33019.

postmortem brain studies reveal a possible common mechanism.” J. Alzheimers Dis. 37:

Hayashi Y, et al. (2011) “A novel, rapid, quantitative cell-counting method reveals

11-21.

oligodendroglial reduction in the frontopolar cortex in major depressive disorder.” Mol.
Psychiatry 16: 1155-1158.

39   

PROJECT / Psychiatry & Behavioral Sciences

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
Tohru KODAMA
Haruo OKADO
Taku MIYAGAWA
Akiyo NATSUBORI
Shinobu HIRAI

Research Assistants
Takashi KOJIMA
Yasuko SEKI
Yoshiko HONDA
Hiroko SHIMBO
Katsuko TAKASAWA

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
Honda M et al(2021) “Evaluation of pathological sleepiness by Multiple Sleep Latency

Miyagawa T et al (2019) “A missense variant in PER2 is associated with delayed sleep-

Test and 24-hour polysomnography in patients suspected of idiopathic hypersomnia.”

wake phase disorder in a Japanese population”. J Hum Genetics, 64(12):1219-1225

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) Metabolome analysis using cerebrospinal fluid from narcolepsy
type 1 patients. Sleep zsaa095.

narcolepsy: an integrated genetic and epigenetic approach.” Sleep 41:zsy019
Toyoda H, et al. (2017) “Narcolepsy susceptibility gene CCR3 modulates sleep-wakepatterns in mice.” PLoS ONE 12:e0187888
Miyagawa T, et al. (2013) “Effects of oral L- carnitine administration in narcolepsy

Shimada M et al. (2020) “Epigenome-wide association study of narcolepsy-affectedpatients: a randomized, double-blind, cross-over and placebo-controlled trial.” PLoS

lateral hypothalamic brain and overlapping DNA methylation profiles between

ONE 8:e53707.

narcolepsy and multiple sclerosis”. Sleep 43(1):zsz198   40

Shimada M, et al. (2018) “Epigenome-wide association study of DNA methylation inPsychiatry & Behavioral Sciences / PROJECT

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
Research Assistants
Yoko HAGINO
Soichiro IDE
Junko HASEGAWA
Shinya KASAI
Daisuke NISHIZAWA Etsuko KAMEGAYA
Yuiko IKEKUBO
Masayo FUJITA
Yuki SERITA
Seii OHKA
Yuko EBATA
Hiroko KOTAJIMA
Kyoko NAKAYAMA
Yuki MORIYA

Students
Yukiko OCHIAI
Yoshihisa KATO
Aimi YAMAGISHI
Masako MORII
Yasuharu YAMAGUCHI
Masato Okitsu
Joei Zou

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. (2021) “Ifenprodil for the treatment of methamphetamine

Ohka S, et al. (2021) “Heparan sulfate 3-O-sulfotransferase 4 is genetically associateduse disorder: An exploratory, randomized, double-blind, placebo-controlled trial.”

with herpes zoster and enhances varicella-zoster virus-mediated fusogenic activity.” Mol

Neuropsychopharmacol Rep. in press.

Pain. 17:17448069211052171.

Sato A and Ikeda K. (2021) “Genetic and environmental contributions to autism spectrum

Nishizawa D, et al. (2021) “Genome-wide association study identifies candidate locidisorder through mechanistic target of rapamycin.” Biol. Psychiatry: Glob. Open Sci. inassociated with chronic pain and postherpetic neuralgia.” Mol Pain 17:1744806921999924

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

Fujita M, et al. (2020) “Increase in excitability of hippocampal neurons during novelty
induced hyperlocomotion in dopamine-deficient mice.” Mol. Brain. 13:126.

the opioid-like receptor NPR-17. Frontiers in Pharmacology, 12:802701

41   

Regeneration of optic nerves after gene therapy. From top
to bottom, one, two and four weeks after treatment

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
Sanada T, et al. (2021) In press “Serologic survey of IgG against SARS-CoV-2 among

Tokunaga Y, et al. (2017) “Selective inhibitor of Wnt/-catenin/CBP signaling ameliorates

hospital visitors without a history of SARS-CoV-2 infection in Tokyo, 2020-2021.” Journal

hepatitis C virus-induced liver fibrosis in mouse model.” Sci. Rep. 7: 325.

of Epidemiology. 32(2):105-111.
Saito M, et al. (2021) “Macrocyclic peptides exhibit antiviral effects against influenza virus
HA and prevent pneumonia in animal models.” Nat Commun. 12(1):2654.

   44

Sanada T, et al. (2016) “Transmission of HBV DNA mediated by ceramidetriggered
extracellular vesicles.” Cell Mol. Gastroenterol Hepatol. 3:272-283.
Yasui F, et al. (2016) “Sensitization with vaccinia virus encoding H5N1 hemagglutinin

Sanada T, et al. (2019) “Avian H5N1 influenza virus infection causes severe pneumonia in

restores immune potential against H5N1 influenza against H5N1 influenza virus.” Sci. Rep.

the Northern tree shrew (Tupaia belangeri).” Virology 529:101-110.

6: 37915.

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
Naoki KAJIWARA

Research Assistants
Ayako TAKASHINO
Masako UKAJI
Namiko NOMURATomoha NISHIZAWA
Wakako MIWATASHI
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
Kobayashi K, et al. (2020) “Heparan sulfate attachment receptor is a major selection

Fujii K, et al. (2018) “VP1 Amino Acid Residue 145 of Enterovirus 71 Is a Key Residue forfactor for attenuated enterovirus 71 mutants during cell culture adaptation.” PLoS

Its Receptor Attachment and Resistance to Neutralizing Antibody during Cynomolgus

Pathog., 18:16(3)e1008428

Monkey Infection.” J. Virol., 92:(15)e00682-18

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

Fujii K, et al. (2013) “Transgenic mouse model for the study of enterovirus 71

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

neuropathogenesis.” Proc. Natl. Acad. Sci. USA., 110: 14753-14758

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

Yamayoshi S, et al. (2009) “Scavenger receptor B2 is a cellular receptor for enterovirus

Attachment Receptor Usage and Neurovirulence in Human Scavenger Receptor B2

71.” Nature Medicine 15:789-801

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
Atsuko KIMURA
Chikako HARADA
Takahiko NORO

Euido NISHIJIMA
Yuta KITAMURA
Naoki KIYOTA
Akiko SOTOZONO

Research Assistants
Mayumi KUNITOMO
Tomoko HARA
Students
Kaori SEGURA

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
Guo, X., Kimura, A., Namekata, K., Harada, C., Arai, N., Takeda, K., Ichijo, H. andHarada, C., Noro, T., Kimura, A., Guo, X., Namekata, K., Nakano, T. and Harada,

Harada,T(2022) “ASK1 signaling regulates phase-specific glial interactions during

T.(2020)“Suppression of oxidative stress as potential therapeutic approach for normal

neuroinflammation.”Proceedings of the National Academy of Science of the United

tensionglaucoma.” Antioxidants 9(9), 874

States of America (PNAS)119(6), e2103812119,
Namekata, K., Guo, X., Kimura, A., Azuchi, Y., Kitamura, Y., Harada, C. and Harada, T.(2020)"Roles of the DOCK-D family proteins in a mouse model of neuroinflammation." Journalof Biological Chemistry 295(19), 6710-6720, 2020.
NNishijima, E., Namekata, K., Kimura, A., Guo, X., Harada, C., Noro, T., Nakano, T. andHarada, T. (2020)“Topical ripasudil stimulates neuroprotection and axon regeneration in
adult mice following optic nerve injury.” Scientific Reports 10(1), 15709,   46

Kimura, A., Noro, T. and Harada, T. (2020) “Role of animal models in glaucoma research.”
Neural Regeneration Research 15(7), 1257-1258

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

Students
Masaki OBA
Nozomi SAKATA
Takuma HARA
Mari KIMURA
Shoya WATANABE

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
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

Akamine T, et al. (2020) “Glycolaldehyde induces sensory neuron death throughBiol. 149:537-543.

activation of the c-Jun N-terminal kinase and p-38 MAP kinase pathways.” Histochem.
Cell Biol. 153:111-119.

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
Daiki KONDO
Ittetsu NAKAJIMA
Terumi ONO

Anri SAITOH
Minato MAEDA

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

Miyaoka Y, et al. (2016) “Using Digital Polymerase Chain Reaction to Detect Single-

RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within

Nucleotide Substitutions Induced by Genome Editing.” Cold Spring Harb. Protoc.

processing bodies.” Nat Commun. 12:6324.

2016:688-692.

Kato-Inui T, et al. (2018) “Clustered regularly interspaced short palindromic repeats

Miyaoka Y, et al. (2016) “Systematic quantification of HDR and NHEJ reveals effects of(CRISPR)/CRISPR-associated protein 9 with improved proof-reading enhances

locus, nuclease, and cell type on genome-editing.” Sci. Rep. 6: 23549.

homology-directed repair.” Nucleic Acids Res. 46: 4677-4688.
Miyaoka Y, et al. (2018) “Detection and Quantification of HDR and NHEJ Induced by
Genome Editing at Endogenous Gene Loci Using Droplet Digital PCR.” Methods Mol.
Biol. 1768: 349-362.

   48

Miyaoka Y, et al. (2014) “Isolation of single-base genome-edited human iPS cells without
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
Research Assistants
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
J Li et al. (2021) “Molecular Level Characterization of Circulating Aquaporin-4 Antibodies

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

in Neuromyelitis Optica Spectrum Disorder” Neurology Neuroimmunology&Neuroinflam

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

mation.

Immunology.

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

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

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

repertoire from millions of lymphocytes.” Nature protocols.

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

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

repertoire formation of identical twins” PNAS.

sequencing and by yeast display of combinatorial VH: VL libraries from immunizedanimals.” mAbs.

49   

PROJECT / Diseases & Infection

Laboratory HeadTakachika HIROI

Takachika Hiroi has been theleader of the laboratory of allergy
and immunology since 2005.
After graduation from Nihon
university school of dentistry
at Matsudo in 1986 (D.D.S.), he
com pl e te d gr a d u a te sc hoolat Nihon university in 1990
(Ph.D). He started to work on
mucosal immunology under
the supervision of Dr. Hiroshi
Kiyono at University of Alabama
at Birmingham, Vaccine center,
Alabama, USA, in 1992. After
returning to Japan, he worked at
Osaka University in 1995-2003
and at University Tokyo in 20032005. His current research is thestudy for effective bio-markers
of sublingual immunotherapy(SLIT) for Japanese cedar pollen
allergy . Further, the molecularmechanisms of mucosal
tolerance still remain unclear. I
want to elucidate this immune
mechanism and develop drugs
for some mucosal diseases in the
future.

AllergyandImmunology
Laboratory HP: https://www.igakuken.or.jp/allergy/

Staff
Researchers
Mayumi SAEKI
Masanobu WATANABE
Tomoe NISHIMURA

Research Assistants
Noriko KITAMURA

Students
Kohei FUSANO
Maho TAMURA
Masato TAMAI
Shotaro NAKAMURA

Research Summary
Recent Topics of Mucosal Immunology
1. Antigen-specific iTreg cells stimulate Th17-mediated colon
inflammation
CD4+ helper T cells play a crucial role in allergy and autoimmune
diseases including inflammatory bowel diseases (IBDs). Th17
cells and Foxp3 + regulatory T cells (Tregs) are thought topromote and suppress inflammatory responses, respectively.
Recently we have developed an antigen-specific and organtargeted inflammation model by transferring antigen-specifichelper T cell subsets followed by antigen administration. By
adopting this strategy to colon, we have shown that antigenspecific Tregs stimulate Th17-mediated inflammation in a CTLA4dependent manner. This finding will call for reconsideration of
Treg/CTLA4-based immunological modulation to suppress ortreat inflammatory diseases.

2. Essential Contribution of CD4+ T Cells to Antigen-Induced
Nasal
Hyperresponsiveness in Experimental Allergic Rhinitis.
Recently, we have reported that CD4+ T cells play a crucial role in
the pathogenesis of AR via induction of NHR, independent of IgE-,
mast cell-, and eosinophil-mediated responses. (A) (B) Antigeninduced NHR in T cell-transferred mice. (C) Administration of ananti-CD4 mAb to immunized mice depleted peripheral CD4+ T
cells almost completely.

Selected Publications
Koyama T, et al. (2021). “Suppressive effect of dexamethasone on murine Th9 cellmediated nasal eosinophilic inflammation. ”Asia Pac Allergy. 11(3):e25. doi: 10.5415/
apallergy.2021.11.e25. eCollection
Tachibana M, et al. (2020). “Ablation of IL-17A leads to severe colitis in IL-10-deficient
mice: implications of myeloid-derived suppressor cells and NO production.” Int Immunol.
32: 187-201.
Kitamura N, et al (2020). “Identification of novel interacting regions involving calcineurin   50

and nuclear factor of activated T cells.” FASEB J. 34: 3197-3208.
Kaminuma O, et al. (2018). “Downregulation of NFAT3 due to lack of T-box transcription
factor TBX5 is crucial for cytokine expression in T cells.” J Immunol. 200: 92-100.
Yokoyama S, et al. (2009) “Antibody-mediated blockade of IL-15 signaling reverses
autoimmune intestinal damage in a mouse model of celiac disease.” Proc. Natl. Acad.
Sci. USA 106: 15849-15854.

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
Naoko YOSHIZAWA
Toyoaki NATSUME
Yuichiro HARA
Saki SAITO

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
Researcher
Syudo YAMASAKI

Researcher
Miharu NAKANISHI

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
Nakanishi M, et al. (2020) “Time investment for program implementation to manage

experiences and depressive symptoms in 10-year-old offspring: A population-basedneuropsychiatric symptoms: an observationallongitudinal study in in-home andbirth cohort study.” Schizophr Res, 206:52-57.

residential care settings.” J Alzheimer's Dis.
Yamasaki S, et al. (2020) “Interaction of adolescent aspirations and self-control on
wellbeing in old age: Evidence from a six-decade longitudinal UK birth cohort.” J Positive
Psychol.
Yamasaki S, et al. (2019) “Maternal diabetes in early pregnancy, and psychotic

Ando S, et al. (2019) “Cohort profile: The Tokyo Teen Cohort study (TTC).”Int J Epidemiol,48(5):1414-1414g.
Nishida A et al.(2018) “A randomized controlled trial of comprehensive early intervention
care in patients with first-episode psychosis in Japan: 1.5-year outcomes from the J-CAP
study.” J Psychiatr Res, 102:136-141.

53   

Social Science & Medicine / Research Center

Unit Leader

Yuki NAKAYAMA

CareerYuki 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
CazzolliPA, BrooksRB, Nakayama Y et al.(2020)The Oral Secretion Scale and Prognostic

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

Factors for Survival in Subjects. With Amyotrophic Lateral Sclerosis. Respiratory Care.

predicts survival in patients with amyotorophic lateral sclerosis” Muscle & Nerve. 59(2)65(8)1063-107

168-173.

Nakayama Y, Shimizu T, Matsuda C, Haraguchi M, et al. (2019) “Body weight variation

Shimizu T, Nakayama Y, et al. (2018) “Sensory cortex hyperexcitability predicts shortpredicts disease progression after invasive ventilation in amyotrophic lateral sclerosis.”

survival in amyotrophic lateral sclerosis.” Neurology 1 ;90(18): e1578-e1587.

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

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   54

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.

•W e 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
property assets, and license promising candidates to industries
for development as medicines, diagnostics, medical devices,
foods, cosmetics and research tools.

•T o promote technology transfer, we introduce seeds andintellectual 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•W e 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

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
Masanari ITOKAWA
Kenichi OSHIMA
Erika SEKI

The 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

Rika KOJIMA
Nobuko UEKI
Tomoko YAGI

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.

Research Support

Public Relations
andOther Activities

59   

TMIMS Programs
Public lectures
Each year we present 8 pubic lectures to informthe public of our research progress and enlighten
people on various medical issues pertinent to theirhealth and welfare. In 2021, we conducted all thelectures on line.
Lecture topics included Dementia, cancer
treatment, brain functions and infectious diseases.

Dementia: Prevention and Early Diagnosis...................Masato HASEGAWA (TMIMS, Dementia Research Project)...................Tetsuaki ARAI (University of Tsukuba)
A challenge for treating cancer: Targeting cancer-causing proteins for degradation...................Yasushi SAEKI (TMIMS, Protein Metabolism Project)...................Mikihiko NAITO (The University of Tokyo)
A new era for genome-based cancer medicine...................Hisao MASAI (TMIMS, Genome Dynamics Project)...................Hiroyuki SASANUMA (TMIMS, Genome Dynamics Project)...................Masatoshi FUJITA (Kyushu University)
Break-through technologies to open new frontier in brain functions...................Yukio NISHIMURA (TMIMS, Neural Prosthetics Project)...................Toshiki TAZOE (TMIMS, Neural Prosthetics Project)...................Shinichi FURUYA (Sony CSL)
Can human win battles with viruese?: a case of Polio virus...................Satoshi KOIKE (TMIMS, Neurovirology Project)...................Hiroyuki SHIMIZU (NIID)
Cancer treatment without pain...................Kazutaka IKEDA (TMIMS, Addictive Substance Project)...................Masahiko SUMITANI (The University of Tokyo Hospital)
How infection occurs: case studies with Coronavirus and Chlamydia...................Kouji KASAHARA (TMIMS, Cell Membrane Laboratory)...................Kentaro HANADA (NIID)
Brain, mind and body of senior citizens: lessons from Lewy Body Dementias...................Masato HASEGAWA (TMIMS, Dementia Research Project)...................Yoshiyuki NISHIO (Tokyo Metropolitan Matsuzawa Hospital)

Science café
In the past ten years we have had 35 special science
presentations geared toward the general public.
These “science cafes” provide people of all ages
with the opportunities to learn, experience, andenjoy science first hand in a casual setting. In 2021,
we had three online science cafes on human bodyoperation and genomes. The participants enjoyed
our online quizzes in these events.

How the human body works; a pediatrician's view...................................................Hiroshi SAKUMA (TMIMS,Child Brain Project)
Seeing and playing with the genome sequences...................................................Hideya KAWAJI(TMIMS,Research Center for Genome &Medical Sciences)
What is the circadian clock? Wonders of a 24-hour rhythm...................................................Hikari YOSHITANE(TMIMS,Circadian Clock Project)   60

Institutional seminars (Igakuken Seminars)
We have institutional seminars on a regular basis. In 2021, despite the continued coronavirus pandemic
we had 18 on line seminars by both domestic and international scientists including those from Yale 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.

Sleep-based treatment of neurodegenerative diseases................Eiko N MINAKAWA (NCNP)
Optical functional neuroimaging in human infant brains................Gentaro TAGA (The University of Tokyo)
Immune responses to SARS-CoV-2................Akiko IWASAKI(Yale University School of Medicine & Howard
Hughes Medical Institute)
Medical research and intellectual property: a case study withregenerative medicine................Masaho ISHINO (Sapporo Medical University)

Combat with COVID-19, a large-scale antibody testing and vaccine
development: a virologist's reflection................Michinori KOHARA(TMIMS, Viral Infection Control Project)
Human systems biology approach to validate "sleep phosphorylation"
hypothesis................Hiroki UEDA (The University of Tokyo)
About the outline of "Ethical Guidelines for Life Science and Medical
Research targeting Humans"................Kaori MUTO (The University of Tokyo)

Development and maintenance of brain: from ascidian to mouse................Haruo OKADO(TMIMS, Laboratory of Neural Development )Introducion of the National Center of Neurology and Psychiatry(NCNP): Aiming to overcome mental, neural, muscular diseases anddevelopmental disorders................Kazuyuki NAKAGOME (NCNP)

Neural activity-dependent gene expression in brain functions................Kanato YAMAGATA(TMIMS, Laboratory of Synaptic Plasticity)

Roles of glucose metabolism in brain aging and neurodegenerative
diseases................Mikiko OKA (Tokyo Metropolitan University)

Rules for distributing synaptic weights in hippocampal neurons................Yukiko GODA (RIKEN)

Epigenome changes and SASP associated with cellular senescence................Akiko TAKAHASHI ( The Cancer Institute Of JFCR)

How scietists publish and advertize scientific papers: Open Access andself-promotion of your paper................Mami YAMADA (Wiley Japan)

Viewing and Understanding Representation of Information in the
Cerebellum: What Do Complex-spikes Represent?
................Takayuki MICHIKAWA (RIKEN)

Molecular Genetic Studies of CNS Vascular Development and Disease................Jeremy NATHANS(Johns Hopkins Medical School)

Diversity of dopamine signals and their functional significance................Masayuki MATSUMOTO (University of Tsukuba)
Mechanism of switching from mitotic to meiotic cell cycle................Kei-ichiro ISHIGURO (Kumamoto University)

Lectures to students
We give lectures to high-school and university students who visit our
institute and we also send staff to visit schools and deliver lectures.
This year, face-to-face lectures were difficult so we gave online

lectures, including one delivered by Takashi SHICHITA on stroke, andthe other by Kohei UENO on brain memory.

Joint programs with universities
Many scientists at TMIMS have joint appointments as visiting professors or lecturers at various
universities. In 2021, we held our annual “open institute” events for prospective graduate students
on line with close to 100 attendants. We currently have 149 students from affiliated universities andother schools, who conduct their research here.

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 provide
them with financial support, and allow them to concentrate on theirstudies 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, 2022