Annual
Reports 2023

Contents
02

Message from the Chairperson

03

Our Mission

04

Message from the Director: TMIMS2023

06 Organizational Chart • Our People at a Glance
07

Meet Our Scientists!

14

Our Goal

16

Research Activities

17

Department of Basic Medical Sciences

18

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

19

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

20

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

21

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

22

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

23

Laboratory of Protein Metabolism........................................................................................................ Yukiko YOSHIDA

25

Department of Brain & Neurosciences

26

Dementia Research Project....................................................................................................................... Masato HASEGAWA

27

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

28

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

29

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

30

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

31

Department of Psychiatry & Behavioral Sciences

32

Schizophrenia Research Project............................................................................................................ Makoto ARAI

33

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

34

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

35

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

37

Department of Diseases & Infection

38

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

39

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

40

Visual Research Project................................................................................................................................ Takayuki HARADA

41

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

42

Regenerative Medicine Project.............................................................................................................. Yuichiro MIYAOKA

43

Cancer Immunology Project..................................................................................................................... Hidetaka TANNO

45

Research Centers

46

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

47

Research Center for Social Science & Medicine/
Unit for Mental Health Promotion......................................................................................................... Atsushi NISHIDA

48

Research Center for Social Science & Medicine/
Unit for Intractable Disease Nursing Care...................................................................................... Yuki NAKAYAMA

49

Research Supports

50

Center for Basic Technology Research

51

Technology Licensing Office

52

Center for Medical Research Cooperation / Molecular Pathology and Histology

53

Public Relations and Other Activities

54

TMIMS Programs

56

Access Map

1   

Message from the Chairperson
Tokyo is the political, economic, and cultural center of Japan.
Thus, improving the health and welfare of the residents ofTokyo is an important step toward building a prosperous future
for Japan. The mission of the Tokyo Metropolitan Institute ofMedical Science (TMIMS) is to promote research in the life andmedical sciences to improve the lives of the citizens of Tokyo.
It is well-known that Japan has the most rapidly aging society
in the world. Tokyo, which reflects Japan itself, is undergoing a
steady increase in cancers, 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
made at the national level. However, it is also essential for the
Tokyo Metropolitan Government to take the initiative in thisendeavor. Tokyo has numerous problems unique to megacities.
For example, high population densities can contribute to socialand mental disorders not commonly seen in other environments
or can breed diseases that can spread explosively throughout
the dense population. TMIMS has been actively working on theseand other important problems, addressing health-related issues
with the aim of protecting the health of all Tokyo citizens.
From early 2020 to the spring of 2023, the highly contagious
COVID-19 disease spread throughout the world causing
unprecedented damage at all levels of society. Combatting
this disease became a top priority. Four years ago, we set up a
“Coronavirus Countermeasures Special Team,” and in cooperation
with the Tokyo Metropolitan Government, we have been making
every effort to develop effective strategies to eliminate thisdisease. Particularly, epidemiological studies such as monitoringof the resident population in the major downtown areas ofTokyo have contributed greatly to the Tokyo Metropolitan
Government's countermeasures against COVID-19 disease,
and we have also pursued our own highly original vaccine
development research against SARS-CoV-2. Today the numberof people infected with SARS-CoV-2 has dropped dramatically,
the threat of COVID-19 disease has greatly diminished, and socialand economic activities have recovered greatly. For the past
four years, many academic interactions have been through web
conferences, but now they are being transformed back to onsite meetings. However, although it has decreased dramatically,
the spread of COVID-19 is still on-going, and TMIMS will needto continue fundamental research in order to develop effective
countermeasures to combat the disease in 2024.
Throughout history there has always been an ongoing struggle
between humans and diseases. In the 21st century, globalizationand international human interactions have greatly accelerated
academic development and the elucidation and disseminationof new knowledge. However, globalization has also allowed
the spread of infectious diseases around the world. Thus, itis critically important for people in the modern world to haveeffective strategies for preventing or minimizing the spreadof infectious diseases and developing effective cures without
curtailing international interactions. This has generated a strongsocial demand for medical advances and solutions. With this goalin mind, scientists at TMIMS will continue to dedicate themselvesto advancing basic and clinical research.
   2

Chairperson

Keiji TANAKA
I am of the opinion that scientific research is a symbol of culture.
A society cannot be considered cultured if it has no interestand knowledge of science and research. Accordingly, TMIMS
aims to be acclaimed both academically and culturally for theknowledge and wisdom of its excellent researchers. Our goal
is to become a symbol of the culture of Tokyo, the foremost
megalopolis in the world. Academic research is often roughly
divided into top-down, exit-oriented, applied research (ofimmediate use), and bottom-up, future-oriented basic research(seemingly not of immediate use). Balancing these two researchstrategies, TMIMS endeavors to operate in a flexible manner inorder to achieve additive and synergistic effects. Top-down andbottom-up research strategies are not incompatible, but canwork in a cooperative and harmonious manner. Throughout thehistory of science, we can find numerous examples of seemingly
useless research suddenly becoming useful, resulting in great
service to society.
Our medical researchers are energetically pursuing their research
to develop preventive medicine and new therapeutic methods toprotect citizens’ health. During this process, TMIMS also plays animportant role in educating young researchers who will continue
to develop human knowledge and contribute to social prosperity.
All staff members of TMIMS are working on research in the life
sciences, ranging from fundamental to practical, using cuttingedge technologies to achieve their goals.
We are working to advance and enrich TMIMS’ research power
to make it a world-premiere research institute that provides
wide-ranging contributions to society. To this end, the entire
staff of TMIMS strives to help pursue incomparable fundamental
research and pass the benefits of this research on to society. At
the same time, we are continuing to recruit and educate talented
people to increase our momentum. Thank you for your support,
which is indispensable for the further development of TMIMS.

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

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

Lifestyle diseases�

Infectious & other diseases�

CancerDementias
Neurodegeneratvie diseases
Diabetes

Pathogenesis・Vaccine
Brain stroke
Spinal cord injury

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

Mental diseases�

Parkinson’s disease
Muscular dystrophy
ALS

MedicalApplications�Collaboration
with hospitals
and industry

Genetic diseases

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

Basic Research�

3   Message fromthe Director: TMIMS 2023
Metropolitan Hospital Organization, which was established in July
2022, and embarked on new collaborative projects with hospitals.
This year, 9 joint research proposals were supported by ourseeds-exploring and joint research programs.
Three special projects (liver cirrhosis, neural prosthesis
technology and vaccine development) endorsed by the Tokyo
Metropolitan Government were conducted. Three programs
commissioned by the Tokyo Metropolitan Government (dementia
care, child abuse prevention and visiting nurse training forpatients with intractable diseases) were also conducted andcontributed to the policy making by the government.
There were two TMiMS International Symposia in 2023. The
24th TMIMS International Symposium, “Early Detection andSocial Intervention for Psychosis and Suicide,” was organized
by Dr. Atsushi Nishida and held on March 17, 2023, and the 25th
TMIMS International Symposium, “Cells and Chromosomes,” wasorganized by me and held on October 16, 2023. Both were heldin-person, as opposed to online, and and included three andsix invited, foreign speakers. The presentations were followedby active discussions. Other public relation-related activities
conducted in 2023 are listed on page 54.
Two years ago, we created a program for inviting prominent
foreign scientists to visit and work at the institute for up to one
year. The program started operating in 2022, and this year, fourscientists, Professor Krassimir Yankulov (University of Guelph,
Canada), Professor Steve Perlmutter (Medical School, Universityof Washington, USA), Professor Robert Barry (Massachusetts
General Hospital and Harvard Medical School, USA), and Dr.
Sung Q Lee (Electronics and Telecommunications ResearchInstitute, South Korea) worked and collaborated with us throughthis program.

Director

Hisao MASAI
Despite the hope for peace in the world, 2023 witnessed another
war that brought devastation to people hoping for a happy life
with their loved ones. It was tragic to see so many innocent
people including small children dying every day. For us living so
far away from the wars, it is easy to bury our heads in the sands
and pretend all this is occurring in another world, but thesetragedies are happening in real time on our planet and we must
all take responsibility and work towards peace and the alleviationof suffering.
In 2023, the COVID pandemic abated and life has somewhat
returned to normal. Face-to-face meetings have resumed, andparties are back. We are very happy to be able to attend real
meetings where we can network, have in-person discussions,and develop new collaborations.
TMIMS 2023
The Center for Medical Research Cooperation made great strides
in promoting collaborative research with Tokyo Metropolitan
hospitals. It developed a close association with The Tokyo   4

Research achievements from our institute in 2023
We are currently in the fourth year of the 4th project term, andhave published many papers in 2023. Most notably, Dr. Tomoyuki
Miyashita and Dr. Minoru Saitoe in the Learning and Memory
Project discovered that glial cells actively transmit sensory
information to higher brain regions in the fruitfly. This transmission
is necessary for learning and memory, and currently Dr. Miyashita
is studying whether similar types of transmission occur inmammals. This study reveals novel roles of glia in informationtransfer and was published in Science. Dr. Akiyo Natsubori fromthe Sleep Disorders Project found that when animals awakenfrom sleep, serotonergic neurons in the dorsal raphe nucleus
induce cortical astrocytes to release more lactate, thus increasing
ATP production in cortical pyramidal neurons. In general, neurons
use more energy when an animal is awake compared to when
it is asleep, and Dr. Natsubori’s work, published in iScience,describes a mechanism through which neurons obtain moreenergy when animals awaken. Dr.Tetsuya Hirabayashi from theLaboratory of Biomembrane identified a novel metabolic pathway
for the production of methyl donors from phosphatidylcholine in
the liver. Methyl insufficiency in mice lacking enzymes involvedin the breakdown of hepatic phosphatidylcholine causes various
adverse effects including growth retardation, reduced weight,
hypoglycemia, hypolipidemia, increased energy consumption
and altered histone/DNA methylation, demonstrating thefunctional importance of this pathway in the availability of methyl

groups. This work was published in Cell Reports. Dr. Daisuke
Yamane from the Viral Infection Control Project discovered anovel biochemical mechanism controlling activity of interferon
regulatory factor 1 (IRF1), a critical factor in immunity. He foundthat CSNK2B, a regulatory subunit of casein kinase 2, binds
directly with IRF1 to regulate downstream effector genes that
inhibit replication of pathogenic hepatitis viruses and flaviviruses(reported in Nucleic Acids Research). Kazuya Toriumi in the
Schizophrenia Research Project identified a novel precursor of
pentosidine, an advanced glycation end-product associatedwith Schizophrenia. Identification of this precursor, glucuronic
acid, suggests novel causes and possible treatments for
Schizophrenia and was published in Redox Biology. Dr. Masato
Hasegawa of the Dementia Research Project has been studying
the connection between amyloid filaments and age-dependentneurodegenerative diseases and contributed to a report in
Nature on the discovery on age-dependent formation of novel
amyloid filaments of a protein, TMEM106B. Other interesting
papers published this year are listed on our Home Page (https://www.igakuken.or.jp/topics/topics2022.html).
Science in 2023
The fight against COVID-19 has continued for over four years and
we are finally seeing an exit from the long depressing days of
isolation, no contact, no direct, face-to-face communication andno parties! At the onset of the outbreak, the immediate need for
vaccines was obvious, but nobody expected that people would
begin to be vaccinated a year later. This was made possibleby the application of mRNA therapy technology. Although theidea for this type of therapy was there as early as 1980s, its
application was hampered by strong inflammatory responses byinjected mRNAs. Katalin Karikó noted that, compared to mRNAs,
tRNAs do not cause significant inflammation when injected. Whatcharacterizes tRNAs is the presence of varieties of modified
bases. This gave Karikó the idea that converting mRNAs to be
more tRNA-like might help reduce inflammatory responses.
She introduced a base modification, pseudo uridine, into an
injected mRNA and observed very little inflammation. Later she
found that the modified mRNA produced much more protein
compared to normal mRNA. These discoveries eliminated the
obstacles to using mRNA for therapy. In 2020, this technology
was used to develop vaccines against SARS-CoV-2, and worldwide vaccination against COVID-19 in less than a year saved
millions of lives and prevented serious cases for many more.
The 2023 Nobel Prize in Physiology or Medicine was awarded to
Katalin Karikó as well as to Drew Weissman for their discoveries
concerning nucleoside base modifications that enabled thedevelopment of effective mRNA vaccines against COVID-19.
I was deeply moved and amazed by the speed with which goals
were set and achieved in the development of these vaccines.
Many factors contributed to this success. Among all, global
collaboration among the scientific community, pharmaceuticalcompanies, and governments was key. The urgency of thepandemic prompted governments and organizations to allocate
significant funding and resources to vaccine development.
Regulatory agencies like the U.S. Food and Drug Administration(FDA) and the European Medicines Agency (EMA) implemented
expedited review processes for COVID-19 vaccines, which
helped in accelerating the approval and distribution of vaccines.
The organized effort through the collaboration of academic,
private, and governmental sections and streamlined efforts withgoal-oriented, rapid decision-making facilitated the process.
Dream for Science
While I was writing this article, the news came out that two-way
star Shohei Ohtani has agreed to a record $700 million (\101billion), 10-year contract with the Los Angeles Dodgers. This iscertainly a genuine dream-come-true story. It feels like ages ago,
but in March 2023, the entire country was crazy about the WBC(World Baseball Classic). All the games gave so much joy andexcitement to children and adults alike. When big baseball stars,
like Nomo, Matsui, Ichiro and Ohtani, left the Japanese BaseballLeague and went to Major Baseball League, baseball critiques
here lamented the loss of quality players and worried about the

decline of the JBL. However, the outcome was the completely
opposite. Looking at Nomo and Matsui as models, children strove
to become star baseball players, and talented athletes continued
to emerge from the JBL to make their own dreams come true.
We need similar dreams in Science. The lack of face-to-facecommunication during the COVID-19 pandemic deprived
teachers and professors of the opportunity of passing on their
dreams to children and students. When Hayabusa returned
to Earth with samples collected from the surface of theasteroid, Itokawa, many, including children, were fascinatedwith space, asteroids, and the long and lonely journey thatHayabusa had taken. This successful 1st mission was followedby the Hayabusa2, which landed on the asteroid, Ryugu, andagain returned successfully with many more samples. The
enthusiasm in Japan was so great that many people applied
during recruitment of astronauts, and the chance of passing thescreening was one out of 2000.
How about our field? Students are not very inclined to follow theacademic path in Japan, seeing their seniors who are struggling
in renewing their positions which last only for 5 years. They
do not see a bright future or “dream” in staying in academia.
We need to inspire young students and convince them that
excitement in Science is something that they can devote your life
to and succeed at.
Outlook for 2024
In 2024, we will be in the final year of the 4th term of project
research. Each project is expected to complete and summarize
its progress. TMiMS, established by the merger of three
medical institutions, each specializing in different branches of
medical research, is unique in its potential to conduct a wide
range of medical research aimed ultimately at developing
new treatments for diseases including cancers, neurologicaldisorders, neurodegenerative diseases, infectious diseases, andmental diseases. We have a strong background in basic medical
research and aim to elucidate the mechanisms of various cellular
operations including protein metabolism, genome maintenance,brain functions, circadian rhythms/aging, memory, and gene
editing, at the molecular level. We strive to understand diseasemechanisms for neurodegeneration, sleep disorders, addiction
and mental diseases, and viral infections. We also use variousorganisms and develop animal models for studies of diseasemechanisms and treatment. We collaborate with hospitals to
expand our studies to humans. For an example, we are trying torestore lost neural connections using ANCs (artificial neuronalconnections). Furthermore, we study social and economic factorsthat may affect the health of individuals within a society. The goalof our studies is to develop novel therapies which will benefit
humankind and to expand human knowledge. Our results could
also aid in policy-making by the Tokyo Metropolitan Government.
Each project is expected to make unique and innovative
discoveries in their fields and make joint efforts with otherresearchers in the institute to explore new horizons in medical
research.
Wishes for 2024
I proposed “Sharing,” “Synergy,” and “Internationalization” askeywords at the start of my term as director. Twelve years after
our founding, we have made much progress in “Sharing” and“Internationalization”. With effective and unique collaborations
within the institute as well as with Tokyo Metropolitan hospitals,
more “Synergy” will be created, facilitating the developmentof truly unprecedented medical research. In 2024, with the endof the pandemic, I expect enhanced constructive interactions
among the scientists of the institute and hope that our institutewill be a place where everyone works in full devotion to researchwith daily excitement and joy.
The world witnessed many tragedies and atrocities in 2023. At
present, there is no sign of a cease-fire in the Ukrainan-Russianor the Israeli-Palestinian conflicts. Many innocent people aredying every day. I can only pray that the brutal wars will cometo an end very soon and people suffering will be able to live in a
warm, safe, and peaceful places with their loved ones.
5   Organizational Chart
Board Chairperson:

Keiji TANAKA
Vice-chairperson: Keiji GOTO

Director General:

Hisao MASAI

Vice Directors General: Masanari ITOKAWA
Minoru SAITOE

Field of Research(Department)

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

Research Center for Genome & Medical Sciences(Hisao MASAI)

Research Center for Social Science & Medecine(Atsushi NISHIDA)

Center for Basic Technology Research(Minoru SAITOE)

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

Secretariat General Manager(Sanae SAKATA)

Our People at a Glance
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663
   6

February 1, 2024

Meet Our
Scientists!

Meet Our Scientists!
Our experiences get stored in our brains as memories and these experiences and corresponding mold our personalities tomake us who we are. Thus, to understand who we are, we need to understand how memories are formed and retained in
the brain. Tomoyuki Miyashita, in the Learning and Memory Project, is working to understand learning and memory using
the fruitfly, Drosophila melanogaster. He trains Drosophila to learn to associate an odor with pain by exposing them to anodor and, at the same time, electrically shocking them. He knows that flies learn this association because they actively
run away from the odor after training. Learning and memory of this association occur in a region of the fly brain called themushroom bodies. While the neuronal pathways and neurotransmitters that transmit odor information to the mushroom
bodies are known, the pathways and transmitters that convey electrical shock information have been unclear. Recently,
Tomoyuki found that shock information is conveyed to the mushroom bodies through glial cells, instead of neurons,
using the transmitter, glutamate. This work was published in Science in an article entitled, “Glia transmit negative valence
information during aversive learning in Drosophila.” We spoke to him about this work.

TomoyukiMiyashita

What was the rationale behind this work?
In order to understand memory formation, we need tounderstand how pain information is conveyed to themushroom bodies. Previously, people proposed that
this information is conveyed by dopaminergic neurons,
which release dopamine onto mushroom body neurons.
But dopamine seems to be a more complex transmitter
involved in synaptic and neuronal plasticity instead ofsimply conveying sensory information. More recent workfrom our lab indicated that glutamate may convey thisinformation rather than dopamine. I wanted to prove
this and also identify the cells that release glutamate
onto mushroom body neurons. There were very few
glutamatergic neurons known to synapse onto themushroom bodies, so I started to look for unidentified
cells that could release glutamate onto the mushroom
bodies. Surprisingly, I found that glial cells, which havetraditionally been thought of as support cells for neurons,
could release glutamate. I then showed that inhibiting
glutamate release from these glial cells prevented
transmission of shock information to the mushroom
bodies, while artificially inducing glutamate release fromglia could mimic the effects of electrical shock during
training.
Why was this result so surprising?
Neurons have always been thought of as the cells that
rapidly transmit information throughout the nervous
system. Glia were either thought of as support cells thatprovided neurons with energy, or as modulatory cells
that allowed neurons to work more efficiently or modified
the signaling of neurons by regulating neurotransmitter
reuptake. Glia were not thought of as cells that directlyor rapidly transmitted information. In fact, it was even   8

debated whether vesicular release of transmittersoccurred from glia. Our work identified a new aspect ofglia that wasn’t previously known.
Why do you think shock information might be transmitted
by glia instead of neurons?
A traditional neuronal synapse involves release of
neurotransmitters from a specific presynaptic neuron toa specific post-synaptic neuron. In other words, theseconnections are one-to-one. A particular neuron may
synapse onto many different neurons by forming manydifferent synapses, but each synapse is one-to-one.
However, there are thousands of different mushroom
body neurons that respond to many different odors. Pain
information needs to be sent to all of these neurons since
flies can form associations between different odors andpain depending on what odor is used during training.
The type of glia that releases glutamate and conveys
shock information is called ensheathing glia. Ensheathing
glia surround or ensheath different mushroom bodycompartments. My data suggest that when flies areshocked, ensheathing glia release glutamate into specificmushroom body compartments. Glutamate diffuses

throughout a compartment binding to a type of glutamate
receptor called NMDA receptors on all neuronal axons
within a compartment. This type of volume release may
be more efficient when conveying information to large
numbers of neurons than traditional one-to-one synapses.
If glutamate is released onto many different neurons, how
can flies learn to run away from one specific odor?
Even though glutamate binds to NMDA receptors
throughout a mushroom body compartment, glutamate
binding by itself isn’t able to activate NMDA receptors.
NMDA receptors are called coincidence detectors
because they require two different stimuli in order tobecome active, glutamate binding and post-synaptic
depolarization. Post-synaptic depolarization occurs uponodor exposure in specific odor-responsive mushroom
body neurons. So, flies learn to run away from an odor if it
is paired with electrical shocks. In the brain, odor exposure
causes depolarization in specific mushroom body neurons
that recognize the odor. If flies are shocked at the sametime, NMDA receptors become active specifically in theseodor-responsive neurons. This specificity is important forforming odor-specific memories.


Written by Jun Horiuchi

aversive stimuli+

aversive stimuli

aversive
stimuli

odor

DAN
EG

KAR
Ca2+

aversive
stimuliDAN
EG

DAN-Ca2+
DA

Glu

KAR
Ca2+

DAR
Ca2+

Mg2+
NMDAR

Mg2+

MB-Ca2+
EG-Ca2+

DA

Glu

DAR

DAN-Ca2+

NMDAR
MB-Ca2+

EG-Ca2+odor
Ensheathing glia transmit aversive information. Aversive stimuli induce vesicular exocytosis from ensheathing glia (EG) and release ofglutamate (Glu) onto kainate receptors (KAR) on dopaminergic neurons (DANs) and NMDA receptors (NMDARs) on mushroom body(MB) neurons. When aversive stimuli are unpaired, Mg2+ block prevents Ca2+ influx (left). When paired with odors, odor-dependent
depolarization removes Mg2+ block allowing Ca2+ influx into appropriate MB neurons (right).

9   Meet Our Scientists!
We spend roughly one third of our lives asleep. Not only that, we also have to sleep regularly, alternating between
sleep and wake cycles every day. Why do we need to sleep? That is the question that drives Akiyo Natsubori in the
Sleep Disorders Project. Recently, she found that an excitatory neurotransmitter, serotonin, which is involved in arousal
and awakening from sleep, also signals astrocytes, support cells in the brain, to provide fuel to neurons to generate
the increased energy used during wakefulness. This work was published in iScience in an article entitled, “Serotonergic
neurons control cortical neuronal intracellular energy dynamics by modulating astrocyte-neuron lactate shuttle.” We
spoke to her about her work.

Akiyo
Natsubori
How did you first become interested in research?
I’ve always been interested in the human brain andconsciousness. My curiosity about sleep stemmed
naturally from this since sleep is a state when we lose
consciousness. As a high school student, I wondered
why we have sleep-wake cycles. What happens to thebrain when we transit between sleep and wake states?
These questions led me to pursue a career as a researchscientist.
What was the rationale for your recent iScience paper?
Neurons are more active when we are awake compared
to when we are asleep. That means that we use moreenergy when we are awake. But curiously, when I
measured amounts of ATP, which is the principal energy
source used in neurons, I found that amounts of ATP
were higher in the cortex of awake animals compared toanimals that were asleep. That means that there must bea tremendous increase in ATP production when animals
awaken, which increases the amount of energy available
when animals are awake. I wanted to find the mechanism
behind this wake-dependent increase in ATP.
   10

How did you do that?
There are several stimulatory neuronal systems that
regulate wakefulness in animals. These systems use
neurotransmitters such as noradrenalin, serotonin,
histamine, or dopamine. When we activate these systems,
they increase arousal in the animal and causes sleeping
animals to awaken. I hypothesized that these systems
may also regulate ATP production, and I tested this using
serotonergic neurons. I first used optogenetics to activate
serotonergic neurons in the dorsal raphe nucleus, which
form extensive axonal connections to neurons in the
cerebral cortex and regulate arousal and wakefulness.
And I found that stimulation of these neurons increases
amounts of ATP in cortical neurons. We also did thereverse experiment of inhibiting activity of these neurons
using chemogenetic methods and found that less ATP
was produced when these animals woke up.
Is the neural pathway that regulates ATP production thesame as the pathway that regulates wakefulness?
Serotonin acts on cortical neurons to regulate
wakefulness, but it acts on astrocytes, which are cells
that support neurons, to regulate ATP production, so they
are different pathways. We found that serotonin induces

Ca2+ and cAMP surges in astrocytes and causes them toproduce lactate. Lactate is an energy source that neurons
use to produce ATP, and lactate produced in astrocytes
is transported to neurons through an astrocyte-neuron
lactate shuttle.
What are the implications of this work?
Although serotonin regulates both wakefulness andenergy production, it does these through different cellularand molecular pathways. This suggests that there may bedifferent states of wakefulness. For example, you might
be awake with lots of energy available, or you might beawake with low energy. We usually think of being awake
as an on/off switch. You are either awake or asleep. But
our work suggests that multiple different pathways might
contribute to the fully awakened state. Interestingly, it’s
been shown that injecting ATP into the brains of micemodels of depression rescues symptoms of depression.
So it’s intriguing to consider that decreased lactate
production in astrocytes might contribute to depression,and increasing activity of the astrocyte-neuron lactate
shuttle might improve symptoms of depression. These
are the current questions that I find interesting.
Interviewed by Jun Horiuchi

Mechanism of regulation of cerebral energy metabolism by serotonergic neurons.
The activation of serotonergic neurons in the dorsal raphe nucleus immediately awakens animals from sleep. Simultaneously, it increases
intracellular ATP levels in excitatory neurons in the cerebral cortex. The mechanism involves serotonin released in the cortex acting
on astrocytes, a type of glial cell, which enhances their Ca2+ and cAMP activities, promoting lactate supply from astrocytes to neurons(astrocyte-neuron lactate shuttle: ANLS). This leads to rapid intracellular ATP synthesis in cortical neurons. MCT2: A lactate transporter inneurons.

11   

Meet Our Scientists!
Schizophrenia is a mental disorder characterized by recurrent psychoses and alterations in perception, thoughts, andbehaviors. While schizophrenia can be treated with antipsychotic medications, its causes are still relatively unknown.
Kazuya Toriumi of the Schizophrenia Research Project is interested in identifying the molecular pathways involved in thedevelopment of schizophrenia. Previously studies from the Schizophrenia Research Project had shown that advanced
glycation end products (AGEs), deleterious products formed by oxidative and carbonyl stresses, are found at high levels
in a large subset of patients with schizophrenia. In particular, pentosidine, an AGE consisting of a crosslink between
arginine and lysine residues in proteins, is found in high amounts in many patients with schizophrenia. Dr. Toriumi wanted
to understand why pentosidine amounts increase in these patients with schizophrenia and identified glucuronic acid asa pentosidine precursor. This work will be helpful in developing more accurate animal and cell models of schizophrenia
and may have positive implications in the development of novel therapies. It was published in Redox Biology in an article
entitled, “Glucuronic acid is a novel source of pentosidine associated with schizophrenia.” We spoke to him about his work
and interest in science.

KazuyaToriumiHow did you first become interested in research andschizophrenia?
I originally wanted to become a high school teacher, butwhen I pursued undergraduate research in college, I
realized that I really enjoy research. Almost 1% of people
are diagnosed with schizophrenia during their lifetime.
My primary interest is in understanding what causes
schizophrenia and helping these people. Furthermore,
I am also interested in understanding how the brain
works. In particular, I want to know how we sense andunderstand the world around us, and schizophrenia
involves an alteration in the way we understand the world,so, if we can figure out what changes in schizophrenia,
we will also gain an understanding of what happens in a“normal” brain.
   12

Why did you focus on pentosidine?
Pentosidine is an advanced glycation end product or
AGE, where a sugar is covalently attached to a protein.
Previously, we found that high amounts of pentosidine
are found in a subset of patients with schizophrenia,
and we think that high pentosidine might be a cause ofsome types of schizophrenia. So, I wanted to know why
pentosidine increases in some people. It’s commonly
thought that high amounts of sugar cause increases inpentosidine and other AGEs, but when we looked atpatients with schizophrenia with high pentosidine, we
didn’t see high levels of sugars or hemoglobin A1c, which
is an indicator of excess sugar in the bloodstream. This led
me to hypothesize that there must be a different pathway
responsible for high pentosidine. If I could find thispathway, it would help us understand what causes some
types of schizophrenia. It would also allow us to makemore accurate cell and animal models of schizophrenia.
How did you identify glucuronic acid as a precursor for
pentosidine?
We did metabolome analyses on patients withschizophrenia with high pentosidine and healthy controls
and looked for differences in metabolites. We found thatin patients with high pentosidine, there was a high amountof glucuronic acid. Pentosidine consists of a sugar bridge
between lysine and arginine amino acids, so we next
mixed lysine, arginine, and glucuronic acid, and we foundthat pentosidine is produced over time. Mixing glucuronic
acid with proteins or plasma also produced pentosidine.
Finally, we showed that injecting glucuronic acid into
guinea pigs caused pentosidine to increase. When we
looked at the correlation between high pentosidine andschizophrenia, we found that an increase of pentosidine
by one standard deviation roughly doubles the chancesthat a person has schizophrenia. An enzyme, aldo-keto
reductase or AKR breaks down glucuronic acid and we
found that AKR enzymatic activity is reduced in patientswith schizophrenia. So, we think that reduced AKR
increases glucuronic acid, which increases pentosidine,
and increases the chances of someone becoming
schizophrenic.
Fascinating! What are your plans for the future?
We’re planning to use this information to make moreaccurate cell and animal models of schizophrenia.
For example, we can knock out AKR in animals anddetermine whether these animals display schizophrenialike phenotypes. I don’t think increasing glucuronic acidon its own is sufficient to cause schizophrenia, but I think
it could be an important step. In addition, we are excited
to be pursuing large-scale cohort studies with Dr. Nishidaat the institute. In these studies, we start with large
cohorts of Tokyo residents starting at 10 years of age
and examine them every two years. Some of the people
in these studies will develop schizophrenia or otherneurological diseases as they age. By looking at cohort
data, we will be able to determine whether high amountsof AGEs or pentosidine at early ages are associated with
development of schizophrenia at later ages.
Interviewed by Jun Horiuchi

Overview of our findings.
Abbreviations: Pentosidine (PEN), glucuronic acid (GlcA), bovine serum albumin (BSA), aldo-keto reductase (AKR).

13   

Ou r Go a l   14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.

15   

Research
Activities

White adipocytes are filled with a large lipid droplet thatoccupies most of the cytoplasm, whereas beige adipocytes
contain multilocular lipid droplets with a high density of
mitochondria.

Basic
MedicalSciences

PROJECT / Basic Medical Sciences

Project Leader

Hisao MASAI

Hisao Masai, the directorgeneralof the institute since 2018,has led the Genome Dynamics
Project since 2009. After
graduating from the Universityof Tokyo in 1981, he worked onmechanisms of DNA replication
as a graduate student under
the supervision of Dr. Ken-ichi
Arai at DNAX Research Institutein Palo Alto, California, USA.
He received his Ph.D. in 1987
from the University of Tokyo,
Graduate School of Science andhas spent his career studying
how genetic information is
duplicated and inherited.
His current interests include
understanding the prototypicalmodes of DNA replication, howbiological stresses contribute totumorigenesis, and how unusual
nucleic acid structures regulate
DNA replication and genome
stability.

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

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

Research Assistants
Naoko KAKUSHO
Rino FUKATSU
Akiko MINAGAWA

Students
Tomoko SAGI
Hao-Wen HSIAO
Trinh Thi To NGO
Manaho SASHIDA
Zheng WANXIN
Ayaka ONUKI
Kosuke YAMAZAKI
Bingyi LI
Lanxin ZHENG
Tatsuki FUKUMOTO

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 replicationin E. coli, fission yeast, and mammalian cells as well as
roles of homologous recombination in DNA damage repair.
Understanding how chromosomes are replicated, repaired,and inherited will allow us to determine how defects in theseprocesses cause diseases, such as cancers, or lead to cellularsenescence. We aim to identify novel target proteins for cancer
treatments and amelioration of age-associated phenotypes.
Specific questions we are addressing:1) How are 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 replication andchromosome architecture?
3) How do various biological stresses induce replication stressand how does this affect genome stability and potentiallycause cancers?
4) What are the roles of replication and checkpoint factors indevelopmental processes?
5) H ow have replication systems evolved and diversified in
response to changing environments?
6) H ow do defects in homologous recombination factors,
BRCA1/2, lead to breast cancer?
7) H ow are endogenous double-stranded breaks in DNA
generated by topoisomerases?
8) How can we develop effective cancer therapies by targeting
replication/checkpoint factors?

A model for chromatin compartmentalization generated by Rif1 near nuclear periphery.
Rif1 protein binds to G4 structures in chromatin and promotes chromatin loop formation
through oligomerization. Rif1 also binds to nuclear membranes directly and throughlipid modification, tethering chromatin fibers to the nuclear periphery. It can also inducecompartmentalization through liquid-liquid phase separation to generate confined, but

Selected Publications

dynamic and interactive chromatin compartments.

Tajima Y. et al. (2024) “Cell fusion upregulates PD-L1 expression for evasion from

Sasanuma H, et al. (2018) "BRCA 1 ensures genome integrity by eliminating estrogen-immunosurveillance” Cancer Gene Ther. 31(1) :158-173.
Kanoh Y, et al. (2023) “Aberrant association of chromatin with nuclear periphery inducedby Rif1 leads to mitotic defect” Life Science Alliance 6(4) : e202201603.
Yoshizawa-Sugata N, et al. (2021) “Loss of full-length DNA replication regulator Rif1 ininduced pathological Topoisomerase II-DNA complexes." Proc. Natl. Acad. Sci. USA, 115(45) : E10642-E10651
You Z and Masai H (2017) “Potent DNA strand annealing activity associated with mouse
Mcm2~7 heterohexamer complex.” Nucleic Acids Res. 45: 6495-6506.

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

Yang C-C, et al. (2016) “Claspin recruits Cdc7 kinase for initiation of DNA replication in

101367.

human cells.” Nature Communications 7: 12135.

Yang C-C, et al. (2019) “Cdc7 activates replication checkpoint by phosphorylating the

Hoa, N.N. et al. (2016) "Mrel 1 is Essential for the Removal of Lethal Topoisomerase 2

Chk1 binding domain of Claspin in human cells.” E-life, 8. pii: e50796

Covalent Cleavage Complexes.” Molecular Cell, 64: 580-592.
Kanoh Y, et al. (2015) “Rif1 binds to G-quadruplexes and suppresses replication over long   18

distances.” Nature Struct. Mol. Biol. 22: 889-897.

Basic Medical Sciences / PROJECT

Project Leader

Yoshiaki KIKKAWA

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

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

Staff
Researchers
Shumpei YASUDA
Yuta SEKI
Ornjira PRAKHONGCHEEP

Research Assistants
Ai TAKAHASHI
Ting MAO
Kayoko TAHARA

Students
Xuehan HOU
Hiroko BEPPU

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
Hou et al. (2023) “Impacts of an age-related hearing loss allele of cadherin 23 on severity

Matsuoka K et al. (2019) “OHC-TRECK: A novel system using a mouse model forof hearing loss in ICR and NOD/Shi mice.” Biochem. Biophys. Res. Commun. 674:147-153.

investigation of the molecular mechanisms associated with outer hair cell death in the

Yasuda SP et al. (2022) “Two loci contribute to age-related hearing loss resistance in theJapanese wild-derived inbred MSM/Ms mice” Biomedicines 10: 2221
Seki et al. (2021) “Myosin VI haploinsufficiency reduced hearing ability in mice.”
Neuroscience. 478:100-111.
Yasuda SP et al. (2020) “c.753A>G genome editing of a Cdh23

ahl

allele delays age-related

hearing loss and degeneration of cochlear hair cells in C57BL/6J mice.” Hear. Res. 389:
107926.

inner ear.” Sci. Rep. 9:5285.
Seki Y, et al. (2017) “A novel splice site mutation of myosin VI in mice leads tostereociliary fusion caused by disruption of actin networks in the apical region of inner
ear hair cells.” PLoS One 12, e0183477.
Miyasaka Y, et al. (2016) “Heterozygous mutation of Ush1g/Sans in mice causes earlyonset progressive hearing loss, which is recovered by reconstituting the strain-specificmutation in Cdh23.” Hum. Mol. Genet. 25: 2045-2059.

19   

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
Ono Y, et al. (2022) “Cryptic splicing events result in unexpected protein products fromOno Y, et al. (2016) “Calpain research for drug discovery: challenges and potential.”

calpain-10 (CAPN10) cDNA.” Biochim. Biophys. Acta Mol. Cell Res. 1869(3): 119188.

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

Shinkai-Ouchi F, et al. (2020) “Calpain-2 participates in the process of calpain-1

Shinkai-Ouchi F, et al. (2016) “Predictions of cleavability of calpain proteolysis byinactivation.” Biosci. Rep., 40: BSR20200552.

quantitative structure-activity relationship analysis using newly determined cleavage sites

Hata S, et al. (2020) “A muscle-specific calpain, CAPN3, forms a homotrimer.” Biochim.
Biophys. Acta, Proteins Proteomics, 7: 140411.
Hata S, et al. (2016) “A gastrointestinal calpain complex, G-calpain, is a heterodimerof Capn8 and Capn9 calpain isoforms, which play catalytic and regulatory roles,
respectively.” J. Biol. Chem., 291: 27313-27322.

   20

and catalytic efficiencies of an oligopeptide array.” Mol. Cell. Proteomics, 15: 1262-1280.
Ono Y, et al. (2014) “The N- and C-terminal autolytic fragments of CAPN3/p94/calpain-3
restore proteolytic activity by intermolecular complementation.” Proc. Natl. Acad. Sci.
USA, 111: E5527-5536.

Basic Medical Sciences / PROJECT

Project Leader

Takahiko HARA

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

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

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

Students
Satoko TAKAGI
Shota HOYANO
Fumiya SEKI
Hikaru ANDO
Riku TAKAHASHI
Yuka EGAWA
Manaka HASEBE
Junta FUNADA

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.

action mechanisms.
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).

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.
In addition, we discovered that CXCL14 plays a critical role inprotecting skin from over-proliferation of S. aureus. We arevigorously investigating physiological roles of CXCL14 and its
Conditional knockout system of ES cells uncovered a novel role of DDX1 in ribosome

Selected Publications

RNA processing which is linked to p53-mediated cell growth control.

Kitajima, K., et al. (2022) “An interferon-γ/FLT3 axis positively regulates hemopoietic

Sato K, et al. (2020) “Nitric oxide and a conditioned medium affect the hematopoietic

progenitor cell expansion from human pluripotent stem cells.” Stem Cells, 40: 906-918.

development in a microfluidic mouse embryonic stem cell/OP9 co-cultivation system.”

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

Micromachines, 11: 305.

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

Kitajima K, et al. (2018) "Domain-specific biological functions of the transcription factor

119: e2116027119.

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

Iwase, R. et al. (2021)“Identification of functional domains of CXCL14 involved in highaffinity binding and intracellular transport of CpG DNA.” J. Immunol., 207: 459.
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.

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.

21   

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
Yuki KATO
Kyohei UEMOTO

Research Assistants
Arisa KURABAYASHI
Visiting Scientist
Yoshitaka FUKADA
Miho YOSHIMURA

Students
Yuta OTOBE
Satoshi KAWAKAMI
Etsuko MITSUYOSHI
Taiki MORIMURA
Anna UCHIDA

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

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

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

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

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

mRNA rhythms.” Communications Biology, 2: 300.

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

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

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

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

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

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

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

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

   22

Laboratory Head

Yukiko YOSHIDA

Yukiko Yoshida is the head of theLaboratory of Protein Metabolism.
She received her Ph.D in 1994
from the Graduate School of
Agricultural and Life Sciences at
the University of Tokyo, and thenworked as a postdoctoral fellow
studying glycobiology at RIKEN(Wako). She has been working at
the Tokyo Metropolitan Instituteof Medical Science since 1997.
In 1999 she identified a novel
glycoprotein-specific ubiquitin
ligase using chemical biology
probes. Her research focus
has been to understand thephysiological functions of theubiquitin system.

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

Staff
Researchers
Akinori ENDO
Hikaru TSUCHIYA
Hiromichi YONEKAWA

Research Assistants
Naoko ARAI
Chikara ANDO
Meari OKADA
Chikage TAKAHASHI
Kyoko UEDA

Research SummaryProtein recycling is essential for our health. All proteins in ourbodies have distinct lifespans after which they are recycled.
Old or defective proteins are identified and tagged with K48linked chains by the ubiquitin system (see figure). K48-linked
polyubiquitin chains target proteins for proteasomal degradation.
Defects in this ubiquitin-proteasome system (UPS) are implicatedin the pathogenesis of various diseases including cancers,
neurodegenerative diseases, infectious diseases and immune
responses, and genetic disorders. Our laboratory studies
mechanisms of ubiquitin signaling and proteasomal degradation
to understand cellular proteostasis and to understand thepathogenesis of these diseases.
To obtain a comprehensive understanding of the ubiquitylation
system, we have developed methods to identify ubiquitylated
substrates (PNAS, 2015) and types of ubiquitin chains (Mol Cell,
2017). We have also studied glycoprotein-specific ubiquitin
ligases in the cytosol, where glycoproteins are normally absent,
and found that ubiquitylation of glycoproteins is involved in thedetection and recycling of damaged organelles (PNAS, 2017).
Moreover, we found that a disease associated with reduced
deglycosylation activity in the cytosol causes accumulation ofubiquitylated glycoproteins and proteasomal dysfunction (PNAS,
2021). Further, we have found that a deubiquitylating enzyme

protects cells from organelle stress (JCB, 2024). Thus, our goal ofunderstanding cellular proteostasis and the ubiquitinproteasome
system is important for understanding the pathogenesis of many
diseases affecting our health.

Ubiquitination is catalyzed by three enzymes, E1, E3, and E3, with E3 providing target
selectivity. This reaction can be repeated to form polyubiquitin chains on substrates.
Different types of ubiquination modification target proteins to different fates. In the
figure, numbers in red indicate the numbers of identified proteins of each type.

Selected Publications
Endo A, et al. (2023) “USP8 prevents aberrant NF-kB and Nrf2 activation by

Yoshida Y, et al. (2017) “Ubiquitination of exposed glycoproteins by SCFFBXO27 directs

counteraciting ubiquitin signals from endosomes.” J. Cell Biol. 223:e202306913.

damaged lysosomes for autophagy.” Proc Natl Acad Sci USA. 114: 8574-8579.

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

Yoshida Y, et al. (2015) “A comprehensive method for detecting ubiquitinated substrates

mediated by sugar-recognizing ubiquitin ligase.” Proc Natl Acad Sci USA. 118: e2102902118.

using TR-TUBE.” Proc Natl Acad Sci USA. 112: 4630-4635.

Tsuchiya H, et al. (2017) “In vivo ubiquitin-type analysis reveals that the Cdc48-Rad23/Dsk2
axis contributes to K48-linked chain specificity of the preoteasome.” Mol Cell 66:488-502.

23      24

Extracellular glutamate imaging in the mushroom body, the memory center ofDrosophila. The extracellular glutamate sensor, iGlusnFR, was expressed in themushroom bodies. When a naïve fruit fly (top panel) is given an electric shock,glutamate is released from glial cells surrounding the mushroom body (bottom panel).

Brain&
Neurosciences

PROJECT / Brain & Neurosciences

Project Leader

Masato HASEGAWA

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

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

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

Research Assistants
Reiko OOTANIMarina TAHIRA

Students
Mina TAKASE
Shohei TAKAKI
Yuta SATO
Syunsuke KANNO

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

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

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

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

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

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

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

ahead of print. (Oct.14)

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

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

Apr;580(7802):283-287.

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

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

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

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

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

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

   26

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 NAGANOSTakahiro ISHIKAWA

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

Students
Maximiliano
Martinez-Cordera
Hinako MURATANI

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

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

Selected Publications
Miyashita et al. (2023). "Glia transmit negative valence information during aversive

Matsuno M, et al. (2015) “Long-term memory formation in Drosophila requires training-learning in Drosophila" Science 382: eadf7429.

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

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

Yamazaki D, et al. (2014) “Glial dysfunction causes age-related memory impairment insynaptic mushroom body neurons evokes non-canonical dopamine release.” J Neurosci.

Drosophila.” Neuron 84: 753-763.

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

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.

memory maintenance and modification in Drosophila mushroom bodies.” Nat.
Commun.7: 13471.

27   

PROJECT / Brain & Neurosciences

Project Leader

Yukio NISHIMURADr. Yukio Nishimura has led theNeural Prosthetics Project since2017. He received a PhD from
Chiba University Medical Schoolin 2003. He was a postdoctoral
fellow at the National Institute forPhysiological Science in Japan
from 2003 and at the Universityof Washington in the US from2007. He started working at the
National Institute for Physiological
Science in 2011, and then joined
the faculty of Kyoto University as
an Associate Professor in 2016.
His overall research is in neuralcontrol of limb movements
in humans and non-humanprimates. His current research
focuses on neural mechanisms offunctional recovery after neuraldamage and restoration of lost
functions using brain computerinterfaces.

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

Staff
Researchers
Yoshihisa NAKAYAMA
Toshiki TAZOE
Sho K. SUGAWARA
Kyuengbo MIN
Osamu YOKOYAMAMichiaki SUZUKI
Postdoctoral fellows
Noboru USUDAKei OBARA
Hironori TSUJI

Research Assistants
Students
Naoko YOSHIDA
Kouichi URAMARU
Shoko HANGUIKokoro KAWAMURA
Yukie AIZAWA
Norihiro IWAMOTO
Sachiko SHIMAKAWA
Sumiko URA
Nao MOTOYANAGI
Tsuta UCHIDA

Research Summary
Our goal is to conceive of innovative ideas for neuro-rehabilitationof lost function 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 supraspinal systems with spinal networks
distal to the lesion to restore lost function. We are conducting
clinical trials to assess the efficacy of ANCs in restoring motor

function in paralyzed patients. We are also investigating theneural 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 remain unknown.
We are identifying these neuronal substrates using humans andanimal models.

Selected Publications   28

Kaneshige et al., Tuning of motor outputs produced by spinal stimulation during

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

voluntary control of torque directions in monkeys. Elife. 2022, 11:e78346.

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

Umeda et al., Temporal dynamics of the sensorimotor convergence underlying

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

voluntary limb movement. PNAS. 2022, 119(48):e2208353119.

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

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.

Brain & Neurosciences / PROJECT

Project Leader

Hiroshi SAKUMA

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

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

Staff
Researchers
Tadayuki SHIMADA
Kuniko KOHYAMA

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Neurosurg. Psychiatr. 86:820-822

29   PROJECT / Brain & Neurosciences

Project Leader

Chiaki OHTAKA-MARUYAMA

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

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

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

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

Students
Hitomi ACHIWA
Ayumu MORIOKA
Kyosuke WADA
Haruka NOMURA
Yusuke SUGITA
Ryoka KATAYAMA
Xianghe SONG
Yurika NOGUCHI
Shouma ISHIZUKA

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 transient neural circuits that involve SpN
and form during development. The proper balance of the
spontaneous activity of the SpN and the activity elicited fromsensory input is essential for brain development, and we want toelucidate the mechanisms involved.”

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

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

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

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

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

   30

Cortical pyramidal neurons expressing
a fluorescent probe for monitoring
intracellular ATP concentration (ATeam;top), and cortical astrocytes expressing afluorescent probe for cytoplasmic calcium
ions (Yellow Cameleon-Nano50; bottom)

Psychiatry&
Behavioral
Sciences31   

PROJECT / Psychiatry & Behavioral Sciences

ください

Project Leader

Makoto ARAI

Makoto Arai has been theleader of the schizophrenia
research project since April
2015. After obtaining his master’s
degree from the Departmentof Biological Science andTechnology at Tokyo Universityo f S c i e n c e , h e o b t a i n e d his
Ph.D. in engineering from Tokyo
University of Science in 2002. Hethen shifted his research focus tomolecular mechanisms causing
schizophrenia as a postdoctoral
fellow under the supervisionof Dr. Masanari Itokawa 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
Kazuya TORIUMI
Hiroaki ISHIDA

Research Assistants
Eriko MAKIYAMA
Koichi TABATA
Hidetoshi TAKAGITomoko INOUE

Students
Yasuhiro MIYANOMai ASAKURA
Tianran WANG
Kyoka IINO
Mayuko MASADA
Azuna OZAWA
Yasufumi TOMITA
Amika YASUMURA

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
Toriumi, K. et al. (2023) Glucuronic acid is a novel source of pentosidine, associated with

Iino K, et al. (2021) “AKR1A1 Variant Associated With Schizophrenia Causes Exon

schizophrenia. Redox biology, 67, 102876.

Skipping, Leading to Loss of Enzymatic Activity.” Front Genet. 12:762999.

Tomita, Y. et al. (2023). Urinary exosomal microRNAs as predictive biomarkers forMiyashita M, et al. (2021) “Fingertip advanced glycation end products and psychotic

persistent psychotic-like experiences. Schizophrenia, 9(1), 14.

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

Tabata, K. et al. (2022). Hair zinc levels and psychosis risk among adolescents.

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

Schizophrenia, 8(1), 107.

in a schizophrenia model system causes mitochondrial dysfunction in the prefrontal

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

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

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

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

Toriumi K, et al. (2022) “Role of glyoxalase 1 in methylglyoxal detoxification-the broadplayer of psychiatric disorders.” Redox Biol. 49:102222.

   32

cortex.”Redox Biology 45: 102057.

association between muscular strength and psychotic symptoms among adolescents.”

Psychiatry & Behavioral Sciences / PROJECT

Project Leader

Makoto HONDA

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

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

Staff
Researchers
Taku MIYAGAWA
Akiyo NATSUBORI
Yoshiki MATSUDA
Tohru KODAMA

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

Visiting Scientist
Mihoko SHIMADA

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.

sleep research fields, we currently have inadequate symptombased 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

Selected Publications
Yoshida-Tanaka K, et al (2023) Narcolepsy type I-associated DNA methylation and

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

gene expression changes in the human leukocyte antigen region. Sci Rep. 2023 Jun

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

28;13(1):10464 .doi: 10.1038/s41598-023-37511-4.

Psychiatry Clin Neurosci 75:149-151

Natsubori A et al. (2022) Serotonergic neurons control cortical neuronal intracellular

Natsubori A, et al (2020) In vivo state-dependent dynamics of cellular energy status inenergy dynamics by modulating astrocyte-neuron lactate shuttle iScience 26, 105830,

cortical neurons. Communications Biol 3: 491

2023 doi: 10.1016/j.isci.2022.105830.

Shimada M, et al (2020) Epigenome-wide association study of narcolepsy-affected

Miyagawa T, et al (2022) A rare genetic variant in the cleavage site of prepro-orexin genelateral hypothalamic brain and overlapping DNA methylation profiles between

is associated with idiopathic hypersomnia. npj Genomic Medicine 7:29 [2022/4/12]

narcolepsy and multiple sclerosis. Sleep 43:zsz198

Honda M, et al (2022) Low carnitine palmitoyltransferase 1 activity is a risk factor for

Shimada M, et al (2020) Metabolome analysis using cerebrospinal fluid from narcolepsy

narcolepsy type 1 and other hypersomnia. Sleep 45:zsac160

type 1 patients. Sleep. 43:zsaa095.

Miyagawa T, et al (2022) A variant in orexin receptor-2 is associated with self-reported
daytime sleepiness in the Japanese population. J Hum Genetics 67:377-380

33   

PROJECT / Psychiatry & Behavioral Sciences

Project Leader

Kazutaka IKEDA

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

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

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

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

Students
Aimi YAMAGISHI
Yasuharu YAMAGUCHI
Masato OKITSU
Joei ZOU
Ryunosuke MARUYAMA
Jun ARAIDA
Yuna KANG
Futaba UMEMURA
Mayuko HAYASHI
Rina AIDA
Rina OKOUCHI

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
Nishizawa D, et al. (2023) “Genome-Wide Association Study Identifies Novel Candidate

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

Variants Associated with Postoperative Nausea and Vomiting.” Cancers (Basel) 15:4729.

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

Kashii H, et al. (2023) “Tsc2 mutation rather than Tsc1 mutation dominantly causes a

Ohka S, et al. (2021) “Heparan sulfate 3-O-sulfotransferase 4 is genetically associatedsocial deficit in a mouse model of tuberous sclerosis complex.” Hum Genomics 17:4.

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

Kotajima-Murakami H, et al (2022). “Exposure to GABAA receptor antagonist picrotox

Pain 17:17448069211052171.

in inpregnant mice causes autism-like behaviors and aberrant gene expression in

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

offspring. ”Front Psychiatry 13:821354

analgesic requirements of opioids in postoperative pain management.” Front Genet
13:815089.

   34

Psychiatry & Behavioral Sciences / PROJECT

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

Head researcher,
independent research group

Shinobu HIRAI

Staff
Shinobu HIRAIJonghyuk PARK
Shoko TAMURA

Hiroko SHIMBO
Kyoko OFUSA
Yayoi ONODERA

Kayoko HIROKADO
Sena UCHIDA
Nobuyuki ARUGA

Research Summary
Sugars are critical to brain function since they are the energy
source required for neurons and glial cells. Our goals are to
elucidate the dynamics of sugar movement in the brain and to
examine how alterations in sugar dynamics affect physiologicalbrain activity to cause or aggravated brain diseases (Figure 1).
Using a mouse model, we recently determined that excess sugar
consumption during adolescence is a potential contributing
factor to psychological disease (Science Advances, doi: 10.1126/
sciadv.abl6077). In these mice, brain capillary angiopathy andimpairment of glucose transport from blood vessels to thebrain parenchyma were observed along with psychiatriclike symptoms. In addition, the connection between sugar
metabolism and Alzheimer’s disease is so strong that Alzheimer’s
disease has been described as a third type of diabetes. These
evidences indicate that breakdowns in metabolic pathways
and sugar homeostasis are almost certain to contribute to thedevelopment and severity of psychological and neurologicaldiseases. Our work will contribute to the development of
new drugs to improve metabolism and novel treatments forpsychological and neurological diseases.

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

Glia

Blood vessel

EEG,
Behavior

Brain parenchyma→ Cells (by FRET probe)

Expression ofhigher brain function

Sugar, Amino acid, etc.
NeuronDevelopment of
new probes

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

Selected Publications
Hirai S.*, Sakuma A, Kunii Y, Shimbo H, Hino M, Izumi R, Nagaoka A, Yabe H, Kojima R,

Hirai S. et al. (2021) “High Sucrose Diets Contribute to Brain Angiopathy with Impaired

Seki E, Arai N, Komori T, Okado H* (2023). Disease specific brain capillary angiopathy in

Glucose Uptake, and Psychosis-related Higher Brain Dysfunctions in Mice” Scienceschizophrenia, bipolar disorder, and Alzheimer's disease. J Psychiatr Res, 163 74-79.

Advances 7: eabl6077.

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

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

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

Psychiatry doi: 10.1038/s41380-023-01941-3.

35   Regenerating axons in mouse optic nerve after injury.
Intraocular injection of DOCK3 activator induced axon
regeneration (bottom) compared to control (top).

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

Naoki YAMAMOTO
Takahiro SANADA
Tomoko HONDA

Research Assistants
Asako TAKAGI
Risa KONO
Sakiko TOYAMA

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
Yamaji K, et al. (2023) “HYPERLINK "https://pubmed.ncbi.nlm.nih.gov/37647690/

Sanada T, et al.(2023)"Antibody response to third and fourth BNT162b2 mRNA booster"Molecular insights of a CBP/-β catenin-signaling inhibitor on nonalcoholic steatohepatitis-

vaccinations in healthcare workers in Tokyo, Japan." J Infect Chemother.29(3):339-346.

induced liver fibrosis and disorder.” Biomed Pharmacother. 166:115379.

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

Toyama S, et al. (2023) ”HYPERLINK "https://pubmed.ncbi.nlm.nih.gov/

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

37545501/"Application of spatial transcriptomics analysis using the Visium system for

macaques and human ACE2 transgenic mice from SARS-CoV-2 and its variants.” Front

the mouse nasal cavity after intranasal vaccination.” Front Immunol. 14:1209945.

Microbiol. 13:967019.

Matsumoto M, et al. (2023) “HYPERLINK "https://pubmed.ncbi.nlm.nih.

Yasui, F, et al. (2022) "Infection with the SARS-CoV-2 B.1.351 variant is lethal in aged

gov/37094077/"CSNK2B modulates IRF1 binding to functional DNA elements and

BALB/c mice.” Sci Rep. 12: 4150.

promotes basal and agonist-induced antiviral signaling.” Nucleic Acids Res. 51(9):44514466.

Sanada T, et al. (2022) "Serologic survey of IgG against SARS-CoV-2 among hospital
visitors without a history of SARS-CoV-2 infection in Tokyo, 2020-2021." Journalof
Epidemiology. 32(2):105-111.

   38

Diseases & Infection / PROJECT

Project Leader

Satoshi KOIKE

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

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

Staff
Researchers
Kyousuke KOBAYASHI

Research Assistants
Masako UKAJI
Namiko NOMURATomoha NISHIZAWA
Sayaka ESAKI
Noriko KITAMURA

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

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

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

initiation of uncoating.

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

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

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

Mice.” J. Virol.,96:(15)e0056122

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

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

Pathog., 18:16(3)e1008428

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

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

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

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

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

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

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

e0151521

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

39   

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
Youichi SHINOZAKI
Xiaoli GUO
Chikako HARADA

Takahiko NORO
Euido NISHIJIMA
Yuta KITAMURA
Naoki KIYOTA
Akiko SOTOZONO

Research Assistants
Mayumi KUNITOMO
Tomoko HARA

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
Shinozaki Y, Namekata K, Guo X, Harada T (2024) “Glial cells as a promising therapeutic

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

target of glaucoma: beyond the IOP.” Frontiers in Ophthalmology 3, 1310226.

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

Namekata K, Tsuji N, Guo X, Nishijima E, Honda S, Kitamura Y, Yamasaki A, Kishida
M, Takeyama J, Ishikawa H, Shinozaki Y, Kimura A, Harada C, Harada T (2023)

factors due to rotenone-induced oxidative stress in Nrf2 knockout mice.” Experimental
Eye Research 226, 109314.

“Neuroprotection and axon regeneration by novel low-molecular-weight compounds

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

through the modification of DOCK3 conformation.” Cell Death Discovery 9, 166.

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

Kiyota N, Namekata K, Nishijima E, Guo X, Kimura A, Harada C, Nakazawa T, Harada
T (2023) "Effects of constitutively active K-Ras on axon regeneration after optic nerve
injury." Neuroscience Letters 799, 137124.
Nishijima E, Honda S, Kitamura Y, Namekata K, Kimura A, Guo X, Azuchi Y, Harada C,
Murakami A, Matsuda A, Nakano T, Parada LF, Harada T (2023) “Vision protection andKashiwagi K, Harada T, Ohnuma S, Koizumi S (2022) "Astrocytic dysfunction induced by
ABCA1 deficiency causes optic neuropathy.” Science Advances 8(44), eabq1081.
Guo X, Kimura A, Namekata K, Harada C, Arai N, Takeda K, Ichijo H, Harada T (2022) “ASK1
signaling regulates phase-specific glial interactions during neuroinflammation.” PNAS
119(6), e2103812119.

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

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

Molecular Therapy 31(3), 810-824.

inhibition of collapsin response mediator protein-2 phosphorylation ameliorates retinal
ganglion cell death in normal-tension glaucoma models.” Genes to Cells 27(8), 526-536.

   40

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
Ryosuke SHINOUCHI

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
Suzuki M, et al. (2023) A Drosophila model of diabetic neuropathy reveals a role ofYako H, et al. (2021) Role of pyruvate in maintaining cell viability and energy production

proteasome activity in the glia. iScience 26:106997.

under high-glucose conditions. Sci. Rep. 11:18910.

Muramatsu K, et al. (2023) Motor skills training-induced activation of descending

Takaku S, et al. (2021) Exendin-4 promotes Schwann cell survival/migration andpathways mediating cortical command to hindlimb motoneurons in experimental

myelination in vitro. Int. J. Mol. Sci. 22:2971.

diabetic rats. Exp Neurol 363:114357.
Osonoi S, et al. (2022) RAGE activation in macrophages and development ofMizukami H, et al. (2020) Role of glucosamine in development of diabetic neuropathy
independent of aldose reductase pathway. Brain Commun. 2:fcaa168.

experimental diabetic polyneuropathy. JCI Insight 7:e160555.

Lee JS, et al. (2019) Arylsulfatase A, a genetic modifier of Parkinson's disease, is an α

Nagai Y, et al. (2022) Rho-associated, coiled-coil-containing protein kinase 1 regulates-synuclein chaperone. Brain 142:2845-2859.

development of diabetic kidney disease via modulation of fatty acid metabolism. KidneyInt. 102:536-545.

*Nakamura S, *Oba M, et al. (2019) Suppression of autophagic activity by Rubicon is asignature of aging. Nat. Commun. 10:847. (*co-first authors)

41   

PROJECT / Diseases & Infection

Project Leader

Yuichiro MIYAOKA

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

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

Staff
Researchers
Tomoko KATO-INUI
Gou TAKAHASHI

Students
Ittetsu NAKAJIMA
Anri SAITOH
Minato MAEDA

Lanyu HUANG
Kayoko SHINOZAKI
Kanata IMAMURA
Yuga YASUDA

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

1) To establish isogenic disease models for cardiomyopathy,
hepatic disease, and neuronal disease to study theirpathogenesis.
2) T o develop therapeutic strategies by transplantation ofgenetically engineered iPS cells to cure genetic disorders.
3) To establish a way to directly manipulate genetic informationin patients’ cells.
4) 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
Nakajima I, et al. (2023) "In Vivo Delivery of Therapeutic Molecules by Transplantation of

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

Genome-Edited Induced Pluripotent Stem Cells.” Cell Transplant. 32:9636897231173734.

(CRISPR)/CRISPR-associated protein 9 with improved proof-reading enhances

Takahashi G, et al. (2022) “Genome editing is induced in a binary manner in single humancells.” iScience. 25:105619.
*Song D, *Takahashi G, et al. (2022) “Retinoids rescue ceruloplasmin secretion andalleviate oxidative stress in Wilson’s disease-specific hepatocytes.” Hum. Mol. Genet.
31:3652-3671.
*Fenix AM, *Miyaoka Y, et al. (2021) “Gain-of-function cardiomyopathic mutations in   42homology-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.
Miyaoka Y, et al. (2016) “Systematic quantification of HDR and NHEJ reveals effects oflocus, nuclease, and cell type on genome-editing.” Sci. Rep. 6: 23549.

RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within

Miyaoka Y, et al. (2014) “Isolation of single-base genome-edited human iPS cells without

processing bodies.” Nat Commun. 12:6324.

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

Diseases & Infection / PROJECT

Project Leader

Hidetaka TANNO

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

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

Staff
Researchers
Mayumi SAEKI
Rikio YABE
Kazuhisa AOKI

Research Assistants
Sayaka ONO
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
K Lee et al. (2023) “Peripheral T cell activation, not thymic selection, expands the T

H Tanno et al. (2020) “Determinants governing T cell receptor α/β-chain pairing infollicular helper repertoire in a lupus-prone murine model” PNAS. 120(48):e2309780120

repertoire formation of identical twins” PNAS. 117(1):532-540.

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

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

Influenza Vaccination” mBio. 13(6):e0254622.

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

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

Immunology. 18(8):889-898

in Neuromyelitis Optica Spectrum Disorder” Neurology Neuroimmunology&Neuroinflam

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

mation. 8(5):e1034.

repertoire from millions of lymphocytes.” Nature protocols. 11(3):429-42.

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

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

Paired VH:VL and TCRβ:TCRα Repertoires.” Science Advances. 6(17):eaay9093

sequencing and by yeast display of combinatorial VH: VL libraries from immunizedanimals.” mAbs. 8(6):1035-44.

43   

ResearchCenters

Research Center / Genome & Medical Sciences

Vice Director

Hideya KAWAJI

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

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

Staff
Director
Hisao MASAI
Senior Researcher
Keisuke OBOKI

Researcher
Nobumasa WATANABE
Naoko YOSHIZAWA
Toyoaki NATSUME
Yuichiro HARA
Saki SAITO
Research Assistant
Ryoko WADA
Naomi IDA

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).

going to tackle these challenges by combining high-throughput
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 are

Selected Publications
Ueno Y, et al. (2023) "Use of clinical variables for preoperative prediction of lymph node

Hirabayashi S, et al. (2019) “NET-CAGE characterizes the dynamics and topology ofmetastasis in endometrial cancer". Jpn J Clin Oncol. hyad135.

human transcribed cis-regulatory elements.” Nat Genet. 51(9):1369-1379.

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 accurate discrimination 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.
Ito Y, et al. (2021) “Nanopore sequencing reveals TACC2 locus complexity and diversityof isoforms transcribed from an intronic promoter.” Sci Rep. 11(1):9355.

Kawaji, H., et al. (2014) “Comparison of CAGE and RNA-seq ranscriptome profiling using clonallyamplified and single-molecule ext-generation sequencing.”Genome Res. 24(4):708–717.
Forrest, A.R.R., Kawaji,H., et al. (2014) “A promoter-level mammalianÞxpression atlas.”Nature, 507(7493):462–70.

   46

Social Science & Medicine / Research Center

Director Unit Leader

Atsushi NISHIDA

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

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

Staff
Researchers
Syudo YAMASAKI
Mitsuhiro MIYASHITA
Kaori BABA

Junko NIIMURA
Satoshi YAMAGUCHI

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

Teen Cohort is a project that

We are promoting the participation

We have developed a care program

scientifically examines how toof people with mental illnesses

to support people with dementia,

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

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

all municipalities in Tokyo.

Selected Publications
DeVylder J, Yamaguchi S, Hosozawa M, Yamasaki S, Ando S, Miyashita M, Endo K,

Hosozawa M, Ando S, Yamaguchi S, Yamasaki S, DeVylder J, Miyashita M, Endo K,

Stanyon D, Usami S, Kanata S, Tanaka R, Minami R, Hiraiwa-Hasegawa M, Kasai K,

Stanyon D, Knowles G, Nakanishi M, Usami S, Iso H, Furukawa TA, Hiraiwa-Hasegawa M,

Nishida A (2023) Adolescent Psychotic Experiences before and during the COVID-19

Kasai K, Nishida A (2023) Sex difference in adolescent depression trajectory before andPandemic: a Prospective Cohort Study. Journal of Child Psychology and Psychiatry, 2023

into the second year of COVID-19 pandemic. Journal of the American Academy of Child

Nov 13. Online ahead of print.

& Adolescent Psychiatry, 2023 Oct 4:S0890-8567(23)02127-5. Online ahead of print.

Narita Z, DeVylder J, Yamasaki S, Ando S, Endo K, Miyashita M, Yamaguchi S, Usami S,

Yamaguchi S, Ando S, Miyashita M, Usami S, Yamasaki S, Endo K, DeVylder J, Stanyon

Stanyon D, Knowles G, Hiraiwa-Hasegawa M, Furukawa TA, Kasai K, Nishida A (2023)

D, Baba K, Nakajima N, Niimura J, Nakanishi M, Hiraiwa-Hasegawa M, Kasai K, Nishida

Uncovering associations between gender nonconformity, psychosocial factors, andA (2023) Longitudinal relationships between help-seeking intentions and depressive

mental health in adolescents: a prospective birth cohort study. Psychological Medicine,

symptoms in adolescents. Journal of Adolescent Health, 73(2023)1061-1067.

1-10.

Okada Y, Yamasaki S, Nishida A, Shibasaki R, Nishiura H (2023) Night-time populationconsistently explains the transmission dynamics of coronavirus disease 2019 in threemegacities in Japan. Frontiers in Public Health, 2023 11, 1163698.

47   Social Science & Medicine / Research Center

Unit Leader

Yuki NAKAYAMA

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

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

Staff
Researchers
Michiko HARAGUCHI
Chiharu MATSUDA
Akiko OGURA
Yumi ITAGAKI

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

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

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

Selected Publications
Shimizu T , Nakayama Y, Hayashi K, et al.(2023) Somatosensory pathway dysfunction

Shimizu T, Nakayama Y, Matsuda C, Haraguchi M, et al. (2019) “Prognostic significance ofin patients with amyotrophic lateral sclerosis in a completely locked-in state. Clinicalbody weight variation after diagnosis in ALS: a single-centre prospective cohort study.”

Neurophysiology 156,253-261,

Journal of Neurology .266(6), 1412–1420

Matsuda C, Shimizu T, Nakayama Y, et al.(2023) Clinical relevance of macroglossia to

Matsuda C, Shimizu T, Nakayama Y, Haraguchi M. (2019) “Cough peak flow decline ratedisease progression in ventilation dependent patients with advanced ALS. Neurol Sci.

predicts survival in patients with amyotorophic lateral sclerosis” Muscle & Nerve. 59(2) 168-173.

44(6):2025-2031
Nakayama Y, Shimizu T*, Matsuda C ,Haraguch M et al. (2022) “Body Weight Gain is Associatedwith the Disease Stage in Advanced Amyotrophic Lateral Sclerosis with Tracheostomy andInvasive Ventilation, Metabolites.” Metabolites 2022, Volume 12, Issue 2, 191CazzolliPA, BrooksRB, Nakayama Y et al.(2020) “The Oral Secretion Scale and Prognostic
Factors for Survival in Subjects. With Amyotrophic Lateral Sclerosis.” Respiratory Care.
65(8)1063-107
Nakayama Y, Shimizu T, Matsuda C, Haraguchi M, et al. (2019) “Body weight variation
predicts disease progression after invasive ventilation in amyotrophic lateral sclerosis.”
Scientific Reports volume 9, s41598-019-48831-9   48

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

ResearchSupports

Research Support

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

Director

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

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

   50

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

51   

Research Support

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

Staff
Kimi UEDA		
Chikako ISHIDA

Hiroko KOUSAKA
Junya MAEDA

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

Molecular Pathology and Histology
Laboratory HP: https://www.igakuken.or.jp/hist_kaiseki/Translational Research using human materials and Management of
Database for Essential Brain Anatomy & Neuropathology

Staff
Researchers
Masato HASEGAWA
Ito KAWAKAMI
Technicians
Erika SEKI
Kentaro ENDO

We mainly study the pathology of neurodegenerative diseases at the molecularlevel and aim to elucidate the pathogenesis of mechanisms. In addition to thefurther promoting neuropathological research, we aim to enhance the support
for each project research and the collaborative research of metropolitan
hospitals, by technicians specializing in neuropathology. Our laboratory features
research use of over 5,000 human neuropathology specimens and samples,one of the largest in the world.
   52

Kazunari SEKIYAMA
Rika KOJIMA
Kyohei MIKAMI
Yoshinobu IGUCHI
Emiko KAWAKAMI
Hiromi KONDO

Students
Araki KIMURA
Akito NAGAKURA

Public Relations
andOther Activities

TMIMS Programs
Public Lectures

TMIMS Seminar Series on "Aging and Health"

Each year we present 8 public lectures to inform the public of our research
progress and enlighten people on various medical issues pertinent to theirhealth and welfare. In 2023, we conducted 9 hybrid lectures.
Lecture topics included diabetes, oxitocine, Calpine, Parkinson’s diseases,
addiction, hearing loss, dementia, and cancer therapies..

In 2022, we had initiated a special TMiMS seminar series,“Aging and Health”, where we have invited prominentscientists in the field, to have lectures of the forefront
research on aging as well as of how to promote healthy
life. In 2023, we initiated the second round of the series“Aging and Health 2”, due to the favorite responses from theviewers. We had 8 lectures for the first round of the series,and 3 for the second round.

Better understanding of type 1 diabetes
What is type 1 diabetes?
.................. Rimei NISHIMURA（ (Jikei University School of Medicine)
Oxytocin known as the ‘Love Hormone’ is effective also for curing inflammation.................. Yasuhiko YAMAMOTO					(Kanazawa University Graduate School of Medical Sciences)
Regulation of calpain in neurodegenerative disease associated with gene mutations
Understanding molecular mechanism of Lissencephaly, a disorder with a brainthat does not have wrinkles.
.................. Masami YAMADA (University of Fukui）)
Functions and relevance to disease of calpains.................. Yasuko ONO (TMIMS)）

Aging and Heakth I and II (11 lectures for each series)
What should we do now to lead healthy, long life?
What should we eat, and how should we excercise, sleep,and care our health?
I-IV. Smart aging.................. Ryuta KAWASHIMA（		(Tohoku University)
I-V. Sleep and life rhythm: Good sleep brings a happy life.................. H ideki TANAKA		(Hiroshima International University)）

Parkinson's disease: basic medical scientist's point of view.................. Atsushi NAMBU (NIPS)

I-VI. What and how to eat: Nutritional science and health.................. Teiji NAKAMURA		
(（Kanagawa University of Human Services)））

iPS cells stories: behind the discovery of iPS cells
iPS cells.................. Kazutoshi TAKAHASHI（ (Kyoto University）)
Impact of the birth of iPS cells.................. Yuichiro MIYAOKA (TMIMS)

I-VII. Training your vision.................. Takayuki HARADA （(（TMIMS）)
I-VIII. Healthy brain from healthy guts
（ yushu University）).................. Nobuyuki SUDO (（（ KAddiction in the modern era
How to deal with the internet game addiction: facts and treatment.................. Ichiro SORA (Kobe University Graduate school of Medicine

I-IX. Training your memory（ MIMS）)）））.................. Minoru SAITOE （(TAddiction: It could be your own problem!
.................. Soichiro IDE (TMIMS)

I-X. Brain fitness: joyful light exercise for heathy and happy life.................. Hideaki SOYA (Tsukuba University)））））

Healthy Hearing and Future Society.................. Hiroshi HIBINO (Osaka University)

I-XI. How does motivation improve your mind and acts?
.................. Yukio NISHIMURA (TMIMS) ）））Preventing Dementia in the Era of 100-Year Life.................. Masahito YAMADA (Kudanzaka Hospital)

II-I. How will you survive the stressful society?
.................. Fuyuki ISHIKAWA (Kyoto University) ）））II-II. How to control your blood sugar level for healthy life?
.................. Kazunori SANGO (TMIMS) ）））II-III. How will you prepare for the era of 100 year life?
.................. Akira IKEGAMI（ (The University of Tokyo)）

Science café
In the past twelve years we have had 44 special science
presentations geared toward the general public. These“science cafes” provide people of all ages with theopportunities to learn, experience, and enjoy science
first hand in a casual setting. In 2023, we had one online
science café on mind and brain, and two face-to-facescience cafes one of which features pigments thatcan be isolated from microorganisms. The participants
enjoyed real experiences of laboratory experiments.

   54

Is your mind controlled by your brain?
..........................Masanari ITOKAWA (TMIMS)
How to make rainbow with things in your refrigerator..........................Yuuka EGAWA, Manaka HASEBE, Junta FUNADA,		

Koji KASAHARA (TMIMS)

Phycocyanin and Chlorophylls: fluorescent pigments from microorganisms..........................Manaka HASEBE , Yuuka EGAWA,
Junta FUNADA, Koji KASAHARA (TMIMS)

Institutional seminars (Igakuken Seminars)
We have institutional seminars on a regular basis. In 2023, coronavirus pandemic has finally subdued, andwe had 29 seminars, (17 in face to face,and 12 on hybrid format) by both domestic and foreign scientists(seven scientists based outside the country) including those from Harvard University and Queen’s University
in UK. We were particularly delighted to have many seminars in a face-to-face manner this year.

Why do animals need to sleep?〜 Studies on vertebrates and invertebrates................Yu HAYASHI (The University of Tokyo)

Hypothalamic supramammillary region in motivated behavior and nicotine................Satoshi IKEMOTO (（ National Institute on Drug Abuse)）

Clonal evolution in the tumor microenvironment.
................Yosuke TOGASHI (Okayama University)

Evolutionary psychology of homocides................Mariko HASEGAWA (Japan Arts Council)

A novel angiogenesis mechanism deciphered by motility analysis ofendothelial cells................Kazuo TONAMI（ (The University of Tokyo) ）Multimodal Optical Interrogation of Neural Circuits Regulating Social
Interactions................Masatoshi INOUE（ (Stanford University)

Developmental mechanisms that contributed to the evolution of
mammalian anatomical features................Tadashi NOMURA(Kyoto Prefectural University of Medicine)

Neural basis underlying behavioral changes across the estrous cycle infemales................Sayaka INOUE (Stanford University)

The art of silence: Replication forks, histone chaperones and genesilencing in S. cerevisiae................Krassimir Joseph YANKULOV（ (University of Guelph)）
Sequence-specific LINE: its strategy for survival and mechanisms oftransposition................Haruhiko FUJIWARA (（The University of Tokyo) ）Dynamic instability of the brain shaped by aging................Masashi TABUCHI (Case Western Reserve University)
Cancer treatment and future prospects: Ongoing activities at the Komagome Hospital................Masakazu TOI (Tokyo Metropolitan Cancer andInfectious Diseases Center Komagome Hospital)
From fMRI of the Brain to Spinal Cord at 7 Tesla................Robert BARRY (Massachusetts General Hospital)

Mechanisms of hibernation in mammals: chipmunk as a model................Nobuhiko TAKAMATSU (Kitasato University)

Neurodegenerative diseases and chaperone-mediated autophagy................Takahiro SEKI (Himeji Dokkyo University)

Interactions between monoamines and glutamate in the antidepressant
response: from the laboratory to the clinic...............Pierre BLIER (University of Ottawa)

Domestic Violence by Husbands against Wives and Children, and its Prevention................Daijyu ABE（ (Psychiatrist)

Mitochondrial aconitase 1 regulates age-related memory impairment via
autophagy/mitophagy-mediated neural plasticity in middle-aged flies................Joong-Jean PARK (Korea University)
Toward understanding the significance and mechanisms of astrocyte
heterogeneity across brain regions................Yuuichi HIRAOKA (Tokyo Medical and Dental University)）
Neural mechanisms underlying stress-induced augmentation of cocaine
cravings and behavioral addictions................Katsuyuki KANEDA (Kanazawa University)
Calpain-3 structure and its role in limb-girdle muscular dystrophy R1.................Peter L. DAVIES (Queen’s University)
Understanding the triplex DNA structure embedded in the genome.
................Shintaro YAMADA (Kyoto University)
The neural cell populations that renew your memory
How is the old memory renewed and updated? 			
................Akinobu SUZUKI (Toyama University / TMIMS)

Generation and implementation of designer cells and animals using
chromosome engineering techniques.
................Yasuhiro KAZUKI (Tottori University)
Elucidating neural stem cell fates from fly to mouse................Tzumin LEE (University of Michigan)
What is start-up business?~ What you need to know as a scientist.
................Megumi TAKATA (Kyushu University)
Construction of an evaluation system for the development of vaccines andtreatments for dengue virus and analysis of the disease mechanism................Meng Ling MOI (The University of Tokyo)
Phenotypic analysis of dystonia musculorum mice with involuntary
movement................Hirohide TAKEBAYASHI (Niigata University)
Overview of 35 years of research on systematic review, meta-analyses,
and randamized controlled trial: How to publish papers in high profile
journals such as BMJ, Lancet, JCO and JAMA?
................Toshiaki FURUKAWA (Kyoto University)

TMIMS International Symposium

Joint programs with universities

In 2023, we were able to have two TMIMS International
Symposia, as shown below. We invited three (24th) and six(25th) foreign scientists, and had a very exciting face-toface presentations and heated discussion.
24th TMIMS International Symposium“Early Detection and Social Intervention for Psychosis andSuicide” organized by Dr. Atsushi Nishida, and 25th TMIMSInternational Symposium “Cells and Chromosomes”
organized by Dr. Hisao Masai.

Many scientists at TMIMS have joint appointments as visiting professors
or lecturers at various universities.
In 2023, for the first time in the last four years. We held our annual“open institute” events
for prospective graduate
students face to face. Morethan 50 students cameto the event, and joined
the lectures and visitedlaboratories. We currently
have 149 students fromaffiliated universities
and other schools, who
conduct their research at
our institute.

We give lectures to high-school and university students
who visit our institute and we also send staffs to visit
schools and deliver lectures. This year, we gave face-toface lectures at Toyama high school delivered by Yoshiaki
Kikkawa.

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.

55   

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, 2024