Annual
Reports 2020

Contents
02 Message from the Chairperson
03 Our Mission
04 Message from the Director:TMIMS2020
06 Team Director,Special Team for COVID-19 Countermeasures
07 Organizational Chart • Our People at a Glance
08 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

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

22

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

23

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

24

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

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 Stroke Renaissance Project................................................................................................................Takashi SHICHITA
31

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

32

Laboratory of Parkinson's Disease................................................................................................Makoto HASHIMOTO

33

Department of Psychiatry & Behavioral Sciences

34

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

35

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

36 Sleep Disorders Project.........................................................................................................................Makoto HONDA
37

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

38 Laboratory of Synaptic Plasticity....................................................................................................Kanato YAMAGATA
39

Laboratory of Neural Development.............................................................................................Haruo OKADO

40 Laboratory of Movement Disorders.............................................................................................Shinji KAKEI
41

Department of Diseases & Infection

42

Viral Infection Control Project...........................................................................................................Fumihiko YASUI43

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

44

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

45

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

46 Regenerative Medicine Project.......................................................................................................Yuichiro MIYAOKA
47

Laboratory of Allergy and Immunology...................................................................................Takachika HIROI

48 Research Centers
49 Research Center for Genome & Medical Sciences..........................................................Hideya KAWAJI
50 Unit for Mental Health Promotion..................................................................................................Atsushi NISHIDA
51

Unit for Intractable Disease Nursing Care...............................................................................Yuki NAKAYAMA

52

Research Supports

53

Center for Basic Technology Research

54

Technology Licensing Office

55

Center for Medical Research Cooperation

56 Laboratory of Neuropathology
57

Public Relations and Other Activities

58 TMIMS Programs
60 Access Map
1   

Message from the Chairperson
Tokyo is the political, economic and cultural center of Japan.
Developing Tokyo into a more healthy welfare state will therefore
go a long way toward building a prosperous future for Japan. The
mission of the Tokyo Metropolitan Institute of Medical Science(TMIMS) is to promote research in the life and medical sciences
to improve the lives and health of the citizens of Tokyo. It is
well known that Japan has the most rapidly aging society in theworld. Tokyo, which reflects Japan itself, is undergoing a steadyincrease in cancers and infectious diseases, lifestyle-related
illnesses, neural and mental disorders, and various other healthproblems. Naturally, curing all of these diseases is a common
goal for all humankind, and considerable efforts have been madeat the national level. However, it is also essential for the Tokyo
Metropolitan Government to take the initiative in this endeavor.
Tokyo has numerous problems unique to megacities. For
instance, many people suffer from rare and intractable diseases
that researchers often overlook. TMIMS has been actively
working on these important problems, promptly and practicallyaddressing health-related issues with the aim of protecting thehealth of all Tokyo citizens.
In 2020, the highly contagious COVID-19 disease spreadthroughout the world causing unprecedented damage at alllevels of society. Combatting this disease is a top priority. At
TMIMS, we swiftly set up a “Coronavirus Countermeasures
Special Team” last year and in cooperation with the Tokyo
Metropolitan Government, we have been making every effort todevelop effective strategies to eliminate this disease. However,
unfortunately, the pandemic is still ongoing and TMIMS willneed to continue fundamental research in order to develop
effective countermeasures to combat the disease in 2021.
Throughout history there has always been an ongoing struggle
between humans and infectious diseases. In the 21st century,
globalization and international human interactions have greatly
accelerated academic development and the elucidation anddissemination of new knowledge. However, globalization has
allowed the spread of infections at unprecedented speeds. Thus,
it is critically important for people in the modern world to haveeffective strategies for preventing infectious diseases, minimizing
their spread, and developing effective cures without curtailinginternational interactions. This has generated a strong social
demand for medical advances and solutions. With this goal inmind, scientists at TMIMS will continue to dedicate themselves toadvancing basic and clinical research.
I am of the opinion that scientific research is a symbol of culture.
A society cannot be considered cultured if it has no interest andknowledge of science and research. Accordingly, TMIMS aims tobe acclaimed both academically and culturally for the knowledge
and wisdom of its excellent researchers. Our goal is to become
a symbol of the culture of Tokyo, the foremost megalopolis in
the world. Academic research is often roughly divided into topdown, exit-oriented, applied research (of immediate use), andbottom-up, future-oriented fundamental research (seemingly   2

Keiji TANAKA
not of immediate use). Balancing these two research strategies,
TMIMS endeavors to operate in a flexible manner in order toachieve additive and synergistic effects. Top-down and bottomup research strategies are not incompatible, but can work in acooperative and harmonious manner. Throughout the history ofscience, we can find numerous examples of seemingly uselessresearch suddenly becoming useful, resulting in great service tosociety.
Our medical researchers are energetically pursuing theirresearch to develop preventive medicine and new therapeutic
methods to protect citizens’ health. During this process, TMIMS
also takes on a role in educating young researchers who willcontinue to develop human knowledge and contribute to social
prosperity. All staff members of TMIMS are working on researchin the life sciences, ranging from fundamental to practical, using
cutting-edge technologies to achieve their goals.
We are working to make TMIMS the world’s premiere research
institute, and advancing and enriching its research power will
create an institute capable of providing wide-ranging services
to society. To this end, the entire staff of TMIMS strives to help
pursue incomparable fundamental research, and pass thebenefits of this research on to society. At the same time, we arecontinuing to recruit and educate talented people to increase ourmomentum. Thank you for your support, which is indispensablefor the further development of TMIMS.

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

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

Lifestyle diseases�

Infectious & other diseases�

CancerDementias
Neurodegeneratvie diseases
Diabetes

Pathogenesis・Vaccine
Brain stroke
Spinal cord injury

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

Mental diseases�

Parkinson’s disease
Muscular dystrophy
ALS

MedicalApplications�Collaboration
with hospitals
and industry

Genetic diseases

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

Basic Research�

3   Message fromthe Director: TMIMS 2020
2020 marks the 9th anniversary of the founding of the Tokyo
Metropolitan Institute of Medical Science (TMIMS) from themerger of three medical institutes that had been operated
independently by the Tokyo Metropolitan Government for morethan 35 years. This year would have been more celebratory forus, but for the unprecedented and devastating pandemic which
has affected all people on earth. 2020 started peacefully withmuch anticipation in Tokyo for the upcoming Olympics, but
ended in a struggle to overcome the pandemic which is stillongoing.
The outbreak of COVID-19 will likely irreversibly change our wayof life. We will have to learn to live with this virus and others fromnow on. What is different now compared to 100 years ago when
the Spanish flu infected 600 million and killed 20-40 million
people is that we now have better scientific tools with which we
can scrutinize viruses, prevent infections, treat infected patients,
analyze infection patterns, and predict the future spread.

Hisao MASAI   4

What can we do to combat COVID-19?
As scientists working in the field of medical science, it is our
responsibility to join worldwide efforts to understand thepathological mechanisms of viral spread, elucidate the causes ofsevere cases, develop drugs to counterattack viral proliferationand treat infection-associated symptoms, and develop effective
vaccines. Indeed, we have organized a special project team in
our institute to combat COVID-19. This team is composed ofthree research/ development groups; vaccine development,
antibody screening, and interdisciplinary research.
1 Vaccine development: We are developing SARS-CoV-2
vaccines based on vaccinia virus vectors which will induce
immunological responses that are longer lasting and moreversatile in dealing with ever changing viruses. We are now at thestage of non-clinical testing and will start clinical testing in 2021.
2 Antibody screening: In collaboration with 14 hospitals in theTokyo Metropolitan district, we have been monitoring SARSCoV-2 antibodies in the general populace to track and monitor
infections. We initiated this project in June and have accumulated
data for more than 20,000 people in the Tokyo Metropolitan
area. Data are reported to the Tokyo Metropolitan Government inorder to design and develop effective policies for preventing the
spread of infections.
3 Interdisciplinary research: Interdisciplinary research includes
analyses of interactions between cellular glycolipids and the viral
Spike protein, development of novel anti-virus drugs targeting
the RNA genome, searches for genetic factors that contributeto serious cases, development of vaccine adjuvants that boost
vaccine efficacy, and proteomic analyses of host responses tovirus infection.
The team also includes various support groups as well as apublic relations group which reports important up-to-datescientific news regarding COVID-19 on our homepage toenlighten the general public.
In addition to these efforts, we are helping the newly establishedTokyo iCDC (Centers for Disease Control and Prevention) by
providing board members with expertise in viral infections,vaccine development, and statistical analyses of infectious
spread.
Despite several hundred papers published every day, SARSCoV-2 is still far from being completely understood. Why does
SARS-CoV-2 cause only mild effects in children? Why are elderly
people more prone to serious cases? Are antibodies against
SARS-CoV-2 short-lived? Why can some people be reinfectedby the virus? What are the host factors that contribute to severe
infections? How do viral mutations affect transmissibility? We are
currently examining these questions in order to help combat thisdisease and bring back the life we enjoyed pre-COVID-19.
The start of a new project term
Research at TMIMS is organized into projects with 5-year goals.
The 3rd project term ended in March 2020 and the 4th term started
this year. We currently have 21 projects and 6 laboratories
organized in four departments: Basic Medical Sciences, Brain &Neurosciences, Psychiatry & Behavioral Sciences, and Diseases& Infections. We also established the Research Center for
Genome & Medical Sciences in 2020. This center will focus on
informatics analyses of genomes for both basic research and forcollaborative research with hospitals aimed at developing novel
diagnostic and therapeutic tools. The Research Center for Social
Science & Medicine was also launched in 2020 to improve ourresearch in social medicine using long-term cohort studies. The
establishment of these centers will enable us to conduct projects
that require support for longer terms and allow us to deal withproblems in a more flexible manner.
Our recent findings
During the 3rd project term, Chiaki Maruyama discovered a novelrole of subplate neurons in development of the six-layered
structure of the cerebral cortex. She discovered that theseneurons form temporary synaptic connections with recently bornneurons to control their migration. This work was published in
Science. Yukio Nishimura and colleagues discovered that the
primary somatosensory cortex receives information about motor
output even before the arrival or sensory feedback signals,
suggesting that this cortex receives anticipatory information
with which it can process somatosensory signals. Keisuke
Kamimura found that Glypican, a heparin sulfate peptide
glycan, is required for experience-dependent synaptic andbehavioral plasticity. This work demonstrates the importance of
extracellular matrix proteins in behaviors. Tomoyuki Miyashita
and Minoru Saitoe identified cellular mechanisms by which
repeated trainings establish long-term memory engram cells,
an important breakthrough in understanding how memories
are formed and stored in the brain. Hikaru Tsuchiya analyzed
different types of ubiquitin linkages and found that the Cdc48Rad23/Dsk2 axis is responsible for directing certain types ofubiquitin-linked substrates to proteasome-dependent protein
degradation. Yukiko Yoshida uncovered a novel mechanism bywhich damaged lysosomes are recycled in cells. These damaged
lysosomes release glycosylated polypeptides which are thenubiquitinated and target lysosomes for autophagic degradation.

Yutaka Kanoh analyzed G-quadruplex structures on genomes
and discovered that they are important elements for generating
higher-order nuclear architecture and for regulating DNA
replication timing by binding to the Rif1 DNA binding protein.
Achievements in 2020
In the 4th research term we have continued making important
findings. Yasushi Saeki and colleagues continued their workon protein ubiquitination and proteasome-dependent protein
degradation and found that under stressful conditions, where
cells have to increase protein degradation, proteasomes andubiquitinated substrates form liquid droplets where protein
degradation occurs. This concentration of protein degradation to
specific nuclei likely enhances efficiency of degradation (featuredin "Meet our scientists!"). Masato Hasegawa, in collaboration
with the MRC Laboratory of Molecular Biology in Cambridge,
UK, reported the structures of α-synuclein filaments fromdifferent human neurodegenerative diseases. This work shows
how non-genetic changes in one protein can cause distinct
diseases with different symptoms. The results from the Saeki
and Hasegawa projects were both published in Nature. Akihiro
Yamano discovered that the optineurin-ATG9 axis is importantin degradation of damaged mitochondria, shedding new lighton cellular pathways by which old or non-functional organelles
are recycled in cells (featured in "Meet our scientists!"). Syudo
Yamazaki and Atsushi Nishida in collaboration with a groupfrom London University, UK, analyzed the results of a 60 year
cohort study and found that adolescents who actively pursued
their aspirations, curiosity and interests expressed greater life
satisfaction at early old ages. Akiyo Natsubori and Makoto Honda
discovered that intracellular ATP levels oscillate during sleepwake states in mouse cortical excitatory neurons. They foundthat ATP levels significantly decrease during REM sleep cycle,
suggesting that energy consumption increases during this periodof sleep.
Despite the COVID-19 pandemic, we have also continued ouroutreach activities, conducting five public lectures and threescience café educational programs online. With the uncertain
outlook for the coming year, we will continue to expand andimprove our online lectures to educate the public on theimportance and excitement of science and research.
Outlook for 2021
Cutting-edge basic medical research will continue to be the key
to the understanding various diseases, developing preventive
and therapeutic measures, and improving physical and mental
health. The strength of our institute is the presence of experts
in wide areas of life sciences and medical sciences who enjoy
research and work together to discover previously unknown
biological phenomena for the benefit of all people. In 2021, we
will continue to strive for new discovery that will contribute to thehealth and welfare of the public.

5   

Team Director, Special
Team for COVID-19
Countermeasures

Vice Director General

Masanari ITOKAWA
The recent severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) pandemic has caused a worldwide public healthemergency. However, SARS-CoV-2 is just the latest of various
epidemics and pandemics that have plagued us throughout
history. In his “Vitae Parallelae,” Plutarch describes the three Csof, closed spaces, crowded places and close-contact settings
that influence contagions, demonstrating humankind’s long andongoing efforts to combat disease transmission. In addition,
many types of folklore and traditional tales have been handed
down describing the correct behaviors for preventing the
spread of disease. The differences between our responses torecent infections compared to those of the past is that since

the beginning of bacteriology in the 19th century, we can utilize
our knowledge that infectious phenomena are caused by small
invisible organisms such as bacteria and viruses.
TMIMS is an organization consisting of over 100 scientists. We
are working to address the SARS-CoV-2 pandemic by vastly
increasing the collaborative efforts of our medical researchteams and increasing the support from our administrative offices
and support divisions. As a Tokyo Metropolitan Institute, we arecoordinating the largest hospital cooperative effort in Tokyo todate encompassing 7,000 beds in 14 metropolitan and public
hospitals in order to protect the citizens of Tokyo from thispandemic.

Joint Meeting of the Task Forces for Antibody Testing andResearch Support   6Organizational Chart
Board Chairperson:

Director General:

Keiji TANAKA
Hisao MASAI

Vice Directors General: Masanari ITOKAWA
Minoru SAITOE

Field of Research(Department)

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

Research Center for Genome & Medical Sciences(Hisao MASAI)

Research Center for Social Science & Medecine(Atsushi NISHIDA)

Center for Basic Technology Research(Minoru SAITOE)

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

Secretariat General Manager(Shinichi NISHIMURA)

Our People at a Glance
Position
Researchers

Number163

Postdoctoral Fellows

51

Students

152

Visiting Scientists

144

Guest Scientists

145

Administrative Staffs

27

Total

682
January 1, 2021

January 1, 2021
7   

Meet our scientists!
When cellular proteins become old and defective, they are degraded. These proteins are first tagged with ubiquitin, amolecule that can be covalently attached to proteins. Specific types of ubiquitination target proteins to proteasomes,
cellular structures that degrade proteins. Sayaka Yasuda, a senior scientist in the Protein Metabolism Project, has been
studying how proteasome-dependent degradation occurs and has obtained intriguing results. She found that when cells
are subjected to certain types of stress, proteasomes congeal into liquid droplet structures in cells, which likely enhances
their ability to degrade substrates. Her results are published in “Stress- and ubiquitin-dependent phase separation of theproteasome,” Nature, 2020 Feb;578(7794):296-300. She spoke to us about her work.

SayakaYASUDAHow did you start this project?
I first learned imaging techniques when I was in
graduate school. When I later joined the Protein
Metabolism Project, proteasome dynamics hadn’t
really been studied before, so I decided to image
proteasomes in cells under a microscope in different
conditions. Proteasomes are usually found diffusely
within a cell, but I found that when cells are stressed,
proteasomes congeal into punctate liquid droplet
structures. That was the start of this work.
What are liquid droplets and why are they important?
They really look like small droplets of oil in water.
Proteasome droplets contain ubiquitinatedproteins, RAD23B (a molecule that shuttles ubiquitin
to proteasomes and bridges their interaction),
proteasomes, and P97 (a molecule required forproteasomal degradation). We think that protein

Hyperosmotic stress-induced proteasome droplets in association with ubiquitinatedproteins in human colon cancer cells. Red, proteasome; green, ubiquitin.
   8degradation occurs in these droplets,and droplets increase the efficiency ofproteasomal degradation by bringing
all the components and targets for
degradation together in a specificlocation.
Does protein degradation become more
important when cells are under stress?
The primary targets that are degradedin our droplets are ribosomal
proteins. When cells are subjected to
hyperosmotic stress, ribosomal proteinsaggregate, and we think that droplets arewhere these aggregates are degraded.
We’ve shown in vitro that ubiquitinatedproteins and RAD23B can form dropletson their own. Proteasomes are recruited
to droplets, but they aren’t necessary
for formation. However, if we add
proteasome inhibitors once droplets areformed, they don’t disperse as readily.
Droplets are transient structures that
disperse once ubiquitinated proteins aredegraded. They last longer than usual if
we inhibit degradation and they disperse
faster if we accelerate degradation.
That’s why we think degradation occurs
in droplets.

How is droplet formation beneficial to cells?
We thought that droplet formation should increase the likelihoodthat a cell would survive hyperosmotic stress, so we performed cell
death assays. However, our RAD23B knockout lines increase cell
death regardless of stress. So, while we think that droplet formation
should improve protein degradation and increase cell survival, but
we haven’t been able to prove that yet. Recently we’ve identified
a sequence in RAD23B that is required for liquid droplet formation.
We’re planning to put a mutation within this sequence to makemutated RAD23B that is unable to form droplets, and we’re planning
to use this mutated protein to prove whether there is a significant
survival benefit to liquid droplet formation in cells.
What is the significance of your work and how does it differ fromprevious reports on liquid droplets?
Liquid droplet formation or liquid-liquid phase separation is asubject that is gaining a lot of attention these days. A relatively wellcharacterized mechanism for liquid phase separation is electrostaticinteractions between proteins or RNAs. The idea is that electrostaticinteractions cause proteins or RNAs to bind together and form
a different phase, separate from other cellular components. Our
results are distinct from previous results because we find thatinteractions between a particular domain of RAD23B and ubiquitin
are responsible for phase separation, not just general electrostaticinteractions. Since ubiquitination is a regulated post-translational
modification, our results suggest that increases in ubiquitination
regulate phase separation. This explains how proteasome droplets
are initially formed, and also explains how they disperse whenubiquitinated proteins are degraded.
9   Meet our scientists!

Authophagic membranes (yellow) encapsulate damaged
mitochondria (red) during mitophagy. Blue, nuclei.

How are old, damaged proteins and organelles degraded in cells? Defects in degradation cause devastating diseases
including Parkinson’s disease in humans. Koji Yamano, a senior scientist in the ubiquitin project at TMIMS has been working
to understand the mechanisms involved in degradation of defective mitochondria. We spoke to him about his latest
research, “Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy,” J Cell Biol 2020 Sep 7.219(9).

Why did you decide to become a research biologist?
As a scientist, we can uncover novel biological mechanisms byusing our hands and by using our ideas and creativity. Everyday is full of scientific activities with many discussions andmany experiments. These kind of things drove me to becomea scientist. When I was a high school student, I was very
interested in chemistry; I didn’t care about biology. But during
my Ph.D. studies, I realized that biology is much more importantfor our health. That’s why I decided to become a molecularbiologist.

Koji
YAMANO   10

How did you become interested in mitochondrial elimination?
Mitochondria have a membrane potential that it uses to
produce ATP. This membrane potential is also important forprotein import. Without a membrane potential, mitochondrial
matrix proteins cannot go into the mitochondria. This isa fundamental principle of mitochondrial protein import.
But in 2008, an interesting paper came out from Richard
Youle’s group at the NIH in the United States. They foundthat a cytosolic protein called Parkin
is selectively recruited to damaged
mitochondria that don’t have a membranepotential and triggers elimination of thesedamaged mitochondria by autophagy.
I’m very interested in this process. How
do mitochondria without a membranepotential recruit Parkin? I wanted toknow the molecular mechanism of
Parkin translocation so I started studying
mitochondrial elimination.
What is the relationship between
Parkinson’s disease and mitochondrial
elimination?
To keep cellular homeostasis, synthesis of
new mitochondria is of course important,
but the degradation of bad mitochondria
is also important. In 2008, Richard Youle’s
group found that Parkin is essential for
mitochondrial elimination. Two years later,in 2010, several groups including ours,
independently identified that PINK1 is alsoessential for elimination and functions
upstream of Parkin translocation.
Surprisingly, Parkin and PINK1 haveboth been identified as products ofgenes mutated in Parkinson’s disease.
Parkinson’s disease is one of the mostfrequent neurodegenerative diseases.
Several papers suggest that accumulationof damaged mitochondria in neuronalcells causes the Parkinson’s diseasephenotype.
What it the relationship between
ubiquitination and mitochondrial
elimination?
Parkin is an E3 ubiquitin ligase, whichmeans that Parkin is an enzyme thatputs ubiquitin onto substrates. In thiscase it puts ubiquitin onto proteins on
damaged mitochondria. Ubiquitin was
primarily known to be important for
degradation of individual proteins bytargeting them to the proteasome, but
recently, we and others found that insome cases, ubiquitination is essential
for the autophagy degradation pathway.
Proteasomes degrade proteins one byone, but autophagy degrades bigger
targets such as protein complexes,
aggregates, and even organelles.

We call autophagy of
mitochondria, mitophagy.
What are the new findings
published in your JCB
paper?
We and others so far
investigated how Parkin
and PINK1 work together toput ubiquitin on damaged
mitochondria. But we still
didn’t know how ubiquitincoated mitochondria
are recognized by the
autophagy machinery.
Autophagy adaptors
may be a key to linking
ubiquitin to the autophagy
machinery. Mammaliancells have five different
autophagy adaptors, andall five adaptors containubiquitin binding domains
and are recruited to themitochondria. Furthermore
all five adaptors contain
ATG8 interacting motifs. ATG8 is a part of the autophagicmachinery that is covalently attached to autophagic
membranes. So many groups thought that autophagy
adaptors could act as a bridging molecule, recruiting ATG8
and autophagic membranes to ubiquinated mitochondria.
However, only two adaptors, called NDP52 and optineurin,
are essential for mitochondrial elimination. We found that
optineurin binds to not only ATG8, but also to anotherautophagy core protein, ATG9, and another group foundthat NDP52 binds FIP200. ATG9 and FIP200 are alsoessential autophagy proteins and they are important forthe de novo synthesis of autophagic membranes. So
now we think that optineurin and NDP52 are recruited
to ubiquitinated mitochondria and begin synthesis of
autophagic membranes to encapsulate the mitochondria.
ATG8 is also important for encapsulation, but we foundthat ATG9-dependent initiation of de novo membrane
synthesis is an important earlier step in this process.

11   Meet our scientists!
Neurodegenerative diseases are thought to be caused by the accumulation of toxic
protein aggregates. For example, aggregates of a protein called α-synuclein cause
diseases known as α -synucleinopathies, which include Parkinson’s disease, dementia
with Lewy bodies, and multiple system atrophy. But how do aggregates of one particular
protein cause three different diseases with different toxicities and symptoms? Genjiro
Suzuki, a senior scientist in the Dementia Research Project has been studying this problem
and recently published his work in a paper, “α-synuclein strains that cause distinct
pathologies differentially inhibit proteasome,” eLife 2020;9:e56825. We spoke to him about
his work.

GenjiroSUZUKI
How did you become interested in science?
When I was a child, my father bought the science magazine, Newton,
each month for me and my brother. This sparked my interest in scienceand led me to study Biology as an undergraduate at the University of
Kyoto and as a graduate student at the University of Tokyo.
What is the relationship between prion protein propagation andneurodegenerative diseases?
Aggregates of proteins such as a-synuclein, tau, and TDP43 arealmost always seen in neurodegenerative diseases, and mutations
that increase the aggregation of these proteins cause familial forms ofthese diseases. That means that these neurodegenerative diseases arelikely caused by these aggregates, similar to how prion diseases arecaused by prion protein aggregates. In neurodegenerative diseases,
degeneration doesn’t occur immediately throughout the brain, butinstead starts at a particular location and spreads in a particularmanner. Again, this is similar to the spread of prion protein aggregates.
That’s why we believe that neurodegenerative disease spread in thebrain in a manner similar to prion propagation.
What are prion proteins?
When a protein is made, it folds into a particular conformation thatallows it to perform its function. However, in some cases, there aredifferent conformations that a protein can fold into. Prion proteinsnormally fold in a native conformation that doesn’t cause disease, butthey can also fold into other harmful conformations. Prion proteins in
harmful conformations can bind to other prion proteins in the native
conformation and shift to the harmful conformation. This causes the
spread of harmful proteins and these proteins get transferred to othercells to spread the disease to other regions of the nervous system.
   12

Synuclein fibers stimulate the formation of phosphorylated and ubiquitinated synuclein
aggregates in primary cultured neuronal cells. Red, synuclein; green, ubiquitin; blue, nuclei.

What are the new findings in your eLife paper?
There are at least three different synucleinopathies,
Parkinson’s disease, dementia with Lewy bodies, andmultiple system atrophy. This suggests that α-synuclein
can fold into at least three different conformations
besides the native conformation. In order to test thisidea, we made α-synuclein in vitro and then aggregatedit under different salt conditions to show that different
aggregates are formed with different characteristics. Our
work shows how aggregation of one protein can cause
different diseases with different symptoms and toxicities.
What is the proteasome and how is it related to toxicity ofaggregated proteins?
Damaged, or deleterious proteins are tagged byubiquitin and this ubiquitin tag directs them to theproteasome where they are degraded. However, in manyneurodegenerative diseases, we see many ubiquitinatedprotein aggregates. We believe that cells try, but fail, todegrade these aggregates, so we decided to measure
the effects of our aggregates on proteasome activity.
We found that our more toxic aggregate abolishedproteasome activity while our less toxic aggregate didn’t.
This shows that one aggregate may be more toxic thanthe other because of the effect it has on the proteasomeand protein degradation.

patients. One of my future plans is to make in vitro
aggregates that are very close to those found in disease
patients. This would allow us to analyze how disease
aggregates inhibit proteasome activity. It would also
be very useful in screening studies to develop newtreatments for these diseases.
Are non-toxic aggregates found in people, and do you
think they could be used to treat diseases?
I don’t think α-synuclein aggregates have been found inpeople without neurodegeneration, but there are reportsof accumulation of tau aggregates in people without
neurodegeneration. So maybe Alzheimer’s patients havetau aggregates that are toxic and inhibit the proteasome,while healthy older people can have tau aggregatesthat aren’t toxic and might even function protectively.
It would be fascinating if we could make non-toxic
protein aggregate seeds that we could use to inhibit theformation of toxic aggregates.

How do you plan to continue this work?
The α-synuclein aggregates we made in vitro are
structurally different from aggregates found in disease13   

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 and clinical researches, that will
help prediction, prevention, diagnosis, and treatment of various diseases
and improve the care of patients, leading to longer healthy life.

15   

Research
Activities

Mouse cochlear inner hair cells, conventional sensory receptors that transmit mostof the acoustic information to the brain. Red cilia represent those lost during aging.

Basic
MedicalSciences

PROJECT / Basic Medical Sciences

Project Leader

Hisao MASAI

Hisao Masai is the director of
TMIMS and the head of the
Genome Dynamics Project. After
graduating from the Universityof Tokyo in 1981, he worked asa graduate student under thesupervision of Dr. Ken-ichi Araiat DNAX Research Institute in
Palo Alto, California, USA, andreceived his Ph.D. in 1987 fromthe University of Tokyo. He has
spent his career studying how
genetic information is duplicatedand inherited, and what happens
when these processes fail.
His current interests include
understanding diversified
modes of DNA replication, howfailure to respond to replicationstress leads to cancerous
growth, and the roles of
unusual nucleic acid structures,
including G-quadruplexes and
RNA-DNA hybrids, in shaping
chromosomes, copying andreading genetic information, andin causing detrimental diseases.

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

Staff
Researchers
Zhiying YOU
Kenji MORIYAMA
Taku TANAKA
Yutaka KANOH
Tomohiro IGUCHI
Yoichi TAJIMA

Postdoctoral fellows
Sayuri ITO
Chi-Chun YANG
Research Assistants
Naoko KAKUSHO
Rino FUKATSU
Akiko MINAGAWA

Students
Karin HORI
Shunsuke KOBAYASHI
Tomoko SAGI
Hao-Wen HSIAO
Kaho TAKASAWA
Naoya INOUE
Hikari MIYAMOTO
Shoha KINOSHITA
Trinh Thi To NGO

Research Summary
Our goal is to understand the molecular mechanisms
responsible for faithful inheritance of genetic materials andstable maintenance of the genome. To achieve this, we are
studying various aspects of chromosome dynamics withparticular emphasis on regulation of DNA replication during
S-phase in E. coli, fission yeast, and mammalian cells. We work to
elucidate how chromosomes replicate and how the inheritanceof replicated chromosomes is regulated to enable stable
maintenance of the genome through generations. Answers tothese questions will shed light on how defects in these processes
contribute to the development of diseases, including cancers,
and to senescence. They will also help to identify novel target
proteins for cancer therapies. We are addressing the following
questions.
1) H ow are the timing and location of DNA replication
determined, and how are these coordinated with otherchromosomal processes?
2) What are the biological functions of G-quadruplex structures,
particularly in regulating DNA replication?
3) How are cellular responses to replication stress regulated,and how are these responses related to other cellular stressresponse pathways?

4) What are the roles of replication factors in development of
individual organs and tissues, and how are these replication
systems diversified to regulate development of different partsof our bodies?

Dbf4/
ASK

Cdc7

Replication stress
ATR

Cancer cells

ClaspinNon-cancer cells

CK1

Chk1

Different mechanisms of replication stress responses in cancerous and non-cancerous
cells. In cancer cells, Cdc7 is primarily responsible for phosphorylation of Claspin, amediator of replication checkpoint, whereas in non-cancer cells, casein kinase 1γ1 isthe primary kinase. This differential mechanism can be exploited to develop a strategy
for cancer cell-specific cell killing by targeting Cdc7 kinase.

Selected Publications
Masai H, et al. (2020) “Detection of cellular G-quadruplex by using a loop structure as astructural determinant.” Biochemical and Biophysical Research Communications, 531,
75-83.
Yang C-C, et al. (2019) “Cdc7 activates replication checkpoint by phosphorylating the
Chk1 binding domain of Claspin in human cells.” E-life, 8. pii: e50796
Kobayashi S, et al. (2019) “Both a unique motif at the C terminus and N-terminal HEAT
repeat contribute to G4 binding and origin regulation by Rif1 protein.” Mol Cell. Biol. 39(4).

   18

pii: e00364-18
You Z and Masai H (2017) “Potent DNA strand annealing activity associated with mouse
Mcm2~7 heterohexamer complex.” Nucleic Acids Res. 45, 6495-6506.
Yang C-C, et al. (2016) “Claspin recruits Cdc7 kinase for initiation of DNA replication inhuman cells.” Nature Communications 7:12135
Kanoh Y, et al. (2015) “Rif1 binds to G-quadruplexes and suppresses replication over long
distances.” Nature Struct. Mol. Biol. 22, 889-897.

Basic Medical Sciences / PROJECT

Project Leader

Yoshiaki KIKKAWA

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

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

Staff
Researchers
Kunie MATSUOKA
Shumpei YASUDA
Yuta SEKI

Research Assistants
Takafumi OUCHI

Students
Ikuo MIURA
Xuehan HOU
Yuichi KOSHIISHI

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

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

The V-shaped stereocilia architecture of

OHC-specific expression of oncomodulin.

OHCs in 1-month-old mice. Stereocilia

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

specifically labeled in the nuclei of OHCs.

green, and magenta) of increasing

Green and blue signals indicate phalloidin

height and form a staircase-shaped

and DAPI staining.

configuration.

Selected Publications
Yasuda SP et al. (2020) “c.753A>G genome editing of a Cdh23ahl allele delays age-related

Seki Y, et al. (2017) “A novel splice site mutation of myosin VI in mice leads tohearing loss and degeneration of cochlear hair cells in C57BL/6J mice.” Hear. Res. 389:

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

107926.

ear hair cells.” PLoS One 12, e0183477.

Matsuoka K et al. (2019) “OHC-TRECK: A novel system using a mouse model for

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

investigation of the molecular mechanisms associated with outer hair cell death in theonset progressive hearing loss, which is recovered by reconstituting the strain-specificinner ear.” Sci. Rep. 9:5285.

mutation in Cdh23.” Hum. Mol. Genet. 25: 2045-2059.

Yasuda SP, et al. (2018) “Effects of genetic background on susceptibility and the

Kikkawa Y and Miyasaka Y. (2016) “Genetic modifiers of hearing loss in mice: The caseacceleration of hearing loss in mice.” An Excursus into Hearing Loss 3–23.

of phenotypic modification in homozygous Cdh23ahl age-related hearing loss.” Monogr.
Hum. Genet. 20: 97–109.

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
Fumiko SHINKAI-OUCHIAya NOGUCHI

Research Assistants
Naoko DOI

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

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

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

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

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

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

quantitative structure-activity relationship analysis using newly determined cleavage

Biophys. Acta, Proteins Proteomics, 7: 140411.

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

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

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

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

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

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

Ono Y, et al. (2016) “Calpain research for drug discovery: challenges and potential.”   20

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

USA, 111: E5527-5536.

Basic Medical Sciences / PROJECT

Project Leader

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

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

Staff
Researchers
Yukiko YOSHIDA
Koji YAMANO
Fumika KOYANO

Postdoctoral fellows
Waka KOJIMA

Students
Anni HUO
Chisato UDAGAWA
Rhota HAYASHIDA

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

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

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

Selected Publications
Yamano K, et al.(2020) “Critical role of mitochondrial ubiquitination and the OPTN-ATG9A
axis in mitophagy.”
J. Cell Biology 219: e201912144.
Koyano F, et al.(2019) “Parkin recruitment to impaired mitochondria for nonselective
ubiquitylation is facilitated by MITOL.”J Biol Chem 294: 10300-10314.
Koyano F, et al.(2019) “Parkin-mediated ubiquitylation redistributes MITOL/March5 frommitochondria to peroxisomes.”

EMBO Rep. 20: e47728.
Yamano K, et al.(2018) “Endosomal Rab cycles regulate Parkin-mediated mitophagy.”
eLife 7: e31326
Okatsu K, et al.(2015) “Phosphorylated ubiquitin chain is the genuine Parkin receptor.”J. Cell Biology 209: 111-128
Koyano F, et al.(2014) “Ubiquitin is phosphorylated by PINK1 to activate Parkin.” Nature
510: 162-166.

21   

PROJECT / Basic Medical Sciences

Project Leader

Takahiko HARA

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

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

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

Students
Miho NAKAGAWA
Chihiro NAKATA
Miyu TANIKAWA
Kaho ISHIGE
Mako HAMASAKI
Satoko TAKAGI
Shota HOYANO
Shoma YAMAGUCHI
Risa SAITO

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

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

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

Selected Publications
Suzuki T, et al. (2020) “A novel all-in-one conditional knockout system uncovered an

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

essential role of DDX1 in ribosomal RNA processing.” Nucl. Acid Res., (in press.)

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

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

753-766.

development in a microfluidic mouse embryonic stem cell/OP9 co-cultivation system.”Tanegashima K, et al. (2017) “CXCL14 acts as a specific carrier of CpG DNA into dendritic

Micromachines, 11: 305.

cells and activates Toll-like receptor 9-mediated adaptive immunity.” EBioMed. 24: 247-

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

256.
Tanegashima K, et al. (2017) “Epigenetic regulation of the glucose transporter geneSlc2a1 by β-hydroxybutyrate underlies preferential glucose supply to the brain of fasted
mice.” Genes Cells 22: 71-83.

   22

Basic Medical Sciences / PROJECT

Project Leader

Yasushi SAEKI

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

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

Staff
Researchers
Akinori ENDO
Hikaru TSUCHIYA
Takuya TOMITA
Emeritus Researcher
Hiromichi YONEKAWA
Visiting Scientists
Fumiaki OHTAKE
Sayaka YASUDA

Supervisor
Keiji TANAKA
Research Assistants
Naoko ARAI
Sayaka ONO
Yasuko KAWASEHarumi SETO
Kyoko UEDA

Students
Shota KOTANI
Miho SAKUMA
Kenta KISAI

Research Summary
The ubiquitin-proteasome system (UPS) is a crucial protein
degradation system that affects almost all cellular functions
in eukaryotic cells. Since protein homeostasis is essential tohuman health, malfunctions of the UPS cause various diseases
including cancers, inflammation, and neurodegeneration. Thus,
UPS regulators are attracting attention as drug discovery targets.
However, there is still much unknown about the UPS. Our goal isto elucidate the fundamental mechanisms of ubiquitin signaling
and proteasomal degradation and to integrate this information
into pathophysiology to develop therapeutic strategies for UPSrelated diseases. To this end, we are currently focusing on thefollowing research projects.
1) D eciphering the ubiquitin code: The structural diversity ofubiquitin chains with distinct topologies, called the ‘ubiquitin
code,’ regulates the diverse functions of ubiquitin. We haveshown that the branching and length of ubiquitin chainsprovide additional specificity to this code (Mol Cell 2016, Nat
Commun 2018). To further investigate the ubiquitin code, weare developing methods to analyze the high-order structure ofubiquitin chains using advanced mass spectrometry.
2) D ecoding mechanisms for proteasomal degradation: We
have identified the p97-UFD1-NPL4 complex and RAD23
family as ubiquitin decoders that direct substrates to theproteasome (Mol Cell 2017, Nat Commun 2019). Currently weare investigating the substrate selectivity of these ubiquitin
decoders using advanced proteomics and by developing
chemical tools to manipulate proteasomal degradation.
3) B iological significance of proteasome phase separation:
Recently, we found the ubiquitin-dependent liquidliquid phase separation (LLPS) of the proteasome under
hyperosmotic stress (Nature). This compartmentalization
appears to be advantageous for the rapid removal ofstress-damaged proteins, and we are further investigating
proteasome phase separation under various stress conditions.
4) G eneration of proteasome mutant mice: Recently, genemutations in the proteasome have been identified in patientswith autism and immune disorders. To understand thepathophysiological mechanism of "proteasomopathy", wegenerated proteasome mutant mice and are analyzing theirphenotypes.

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

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

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

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

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

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

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

Rad23/Dsk2 axis contributes to K48-linked chain specificity of the proteasome.” Mol.

Tsuchiya H, et al. (2018) “Ub-ProT reveals global length and composition of protein
ubiquitylation in cells.” Nat. Commun. 9, 524.

Cell 66, 485-502.
Ohtake F, et al. (2016) “The K48-K63 branched ubiquitin chain regulates NF-κB
signaling.” Mol. Cell 64, 251-266.

23   

Laboratory / Basic Medical Sciences

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

Laboratory HeadKohji KASAHARA

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

Staff
Researchers
Ikuo KAWASHIMA
Kiyoshi OGURA
Tetsuya HIRABAYASHI
Keisuke KOMATSUYANorihito KIKUCHI

Students
Mai KAWAGUCHI
Jun KANBE

Research Summary
We are studying the function of lipid rafts. Lipid rafts are dynamic
assemblies of glycosphingolipids, sphingomyelin, cholesterol,and proteins that can be stabilized in microdomains on cellsurfaces. They are involved in the regulation of a number ofcellular processes including axonal guidance, cellular migration,and blood clot formation and retraction.
In order to understand how lipid rafts receive external signals andtransduce them to internal changes, we have been identifying
protein interactions of glycosphingolipids in cerebellar granulecells from the nervous system, and in platelet cells from theblood.

signals through interactions with Lyn/Cbp proteins found inganglioside GD3-rich rafts of cerebellar granule cells. We further
found that the chemokine SDF-1α triggers the chemoattractionof cerebellar granule cells during cerebellar development.
SDF-1α stimulates GTPγS binding to Goα, and causes Goαtranslocation to lipid rafts, leading to growth cone collapse of
cerebellar granule cells.
In blood platelets, sphingomyelin-rich lipid rafts are important for
both blood clot formation and retraction through interaction withfibrin. We have identified a factor XIII-dependent fibrin-integrin
αIIbβ3-myosin axis in sphingomyelin-rich membrane rafts that is
important in clot retraction.

In cerebellar granule cells we found that anti-ganglioside GD3
antibodies co-precipitate the GPI-anchored neural cell adhesion
molecule TAG-1, the src-family kinase Lyn, its substrate Cbp,
and the trimeric G protein Goα. TAG-1 is important for axonal
guidance, and cellular migration. However, GPI anchors have no
direct contact with the cytoplasm so it was unclear how TAG1 activation causes internal cellular changes required for axonal
guidance or migration. We demonstrated that TAG-1 transduces

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

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

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

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

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

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

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

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

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

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

Blood 115, 1277-1279.

GD3 in rat brain. Possible regulation of Lyn by glycosphingolipid in caveolae-likeYuyama K, et al. (2007) “Translocation of activated heterotrimeric G protein Gαo to   24domains.” J.Biol.Chem. 272, 29947-29953.

Neurofibrillary changes in Alzheimer's disease brain.
Black, tau aggregates stained by Gallyas-Braak staining; pink, nuclei.

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
Masato HOSOKAWA
Masami SUZUKAKE
Fuyuki KAMETANI
Ito KAWAKAMI

Postdoctoral fellows
Taeko KIMURA
Ryu KATSUMATA
Research Assistants
Reiko OOTANI

Students
Ryohei WATANABE
Sei IMURA
Yuuya HANZAWA
Mina TAKASE

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

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

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

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

Selected Publications
Zhang W, et al. Novel tau filament fold in corticobasal degeneration. Nature 2020

Watanabe R, et al. Intracellular dynamics of Ataxin-2 in the human brains with normal

Apr;580(7802):283-287.

and frontotemporal lobar degeneration with TDP-43 inclusions. Acta Neuropathol

Masuda-Suzukake M, et al. Dextran sulphate-induced tau assemblies cause

Kametani F, et al. Comparison of common and disease-specific post-translational

2020 Jul 8;2(2):fcaa091.

modifications of pathological tau associated with a wide range of tauopathies. Front

Suzuki G, et al. α-Synuclein strains that cause distinct pathologies differentially inhibit

Neurosci 2020, 581936.

proteasome. eLife. 2020 Jul 22;9:e56825.

Hasegawa M. Experimental models of prion-like protein propagation. Neuropathology.

Schweighauser M, et al. Structures of α-synuclein filaments from multiple system
atrophy. Nature 2020 Sep; 585(7825):464-469 .

   26Commun 2020 Oct 28;8(1):176.

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

2020 Jun 1.

Brain & Neurosciences / PROJECT

Project Leader

Minoru SAITOE

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

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

Staff
Researchers
Kohei UENO
Tomoyuki MIYASHITA
Motomi MATSUNO
Shintaro NAGANOSYoshinori SUZUKI
Postdoctoral fellows
Hiroshi KUROMI

Research Assistants
Kyoko OFUSAEmi KIKUCHI
Saki KOMIYATomoko TAKAMISAWA

Students
Nozomi UEMURA

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

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

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

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

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

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

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

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

27   

PROJECT / Brain & Neurosciences

Project Leader

Yukio NISHIMURA

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

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

Staff
Researchers
Yoshihisa NAKAYAMA
Toshiki TAZOE
Osamu YOKOYAMASho K. SUGAWARA
Michiaki SUZUKI

Postdoctoral fellows
Miki KANESHIGE
Rumiko OKAMOTO
Noboru USUDA
Research Assistants
Naoko YOSHIDA
Shoko HANGUI

Yukie AIZAWA
Sachiko SHIMAKAWA
Tomomi GOTO
Students
Kei OBARA
Naoya KABE
Kouichi UAMARU

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

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

Selected Publications   28

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

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

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

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

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

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

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

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

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

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

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

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

Brain & Neurosciences / PROJECT

Project Leader

Hiroshi SAKUMA

Hiroshi Sakuma has been theleader of the Child Brain Projectsince 2015. He obtained his MD(1993) and PhD (2005) degrees
from Tokyo Medical and
Dental University and trainedin pediatric neurology at the
National Center of Neurology
and Psychiatry. He then studied
neuroimmunology at the National
Institute of Neuroscience with
Prof. Sachiko Miyake in 2010,and has been involved in Health
Labour Sciences Researchon virus-associated acuteencephalopathy since 2010. He
has been working at the Tokyo
Metropolitan Institute of Medical
Science since 2012. His current
interests include 1) mechanismsof virus-associated acuteencephalopathies including
febrile infection-related epilepsy
syndrome, 2) biomarkers forpediatric immune-mediatedneurological diseases, and 3)
generating an international
consensus on pediatricautoimmune neurologicaldiseases.

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

Staff
Researchers
Kuniko KOHYAMA
Visiting scientists
Hiroko TADA
Ai HOSHINO
Misato TSUBOITomonori SUZUKI
Naoyuki TANUMA
Masaharu HAYASHI

Research Assistants
Mariko OZAKI

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

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

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

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

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

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

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

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

epilepsy syndrome.” Ann. Clin. Transl. Neurol. In press.

J. Neuroinflammation 14:109

Mizuguchi M, et al. (2020) “Guidelines for the diagnosis and treatment of acuteNakahara E, et al. (2015) “A diagnostic approach for identifying anti-neuronal antibodies

encephalopathy in childhood.” Brain Dev. In press.

in children with suspected autoimmune encephalitis.” J. Neuroimmunol. 285:150-155.

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

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

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

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

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

Neurosurg. Psychiatr. 86:820-822

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

29   

PROJECT / Brain & Neurosciences

Project Leader

Takashi SHICHITA

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

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

Staff
Researchers
Seiichiro SAKAI
Jun TSUYAMA

Research Assistants
Yoshiko YOGIASHI
Kumiko KURABAYASHI

Students
Koutaro NAKAMURA
Akari NAKAMURA
Kento OTANI

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

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

Selected Publications   30

Tsuyama J, et al. (2018) “Pivotal role of innate myeloid cells in cerebral post-ischemic

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

sterile inflammation.” Semin. Immunopathol. 40(6): 523-538.

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

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

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

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

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

Brain & Neurosciences / PROJECT

Project Leader

Chiaki Ohtaka-MARUYAMA

Chiaki Ohtaka-Maruyama
obtained her Ph.D. in Biology
from the University of Tokyo.
After postdoctoral training at
NEI, NIH (Bethesda, MD, USA)and RIKEN (Wako), she becamea Research Scientist at theTokyo Metropolitan Institutefor Neuroscience in 2006. She
studies neural development
and has been the project
leader of the Developmental
Neuroscience Project since2019. Her research focuses onunderstanding the molecular andcellular mechanisms of corticaldevelopment and evolution. In
particular, she is interested in
how the mammalian six-layer
cortical structure developed
during evolution. Using timelapse imaging and functional
analyses, she found novel
functions of subplate neurons
in regulating radial neuronalmigration.

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

Staff
Researchers
Keisuke KAMIMURA
Takuma KUMAMOTO

Research Assistants
Kumiko HIRAI
Aiko ODAJIMA
Yoshiko TAKAHSAHI
Kaori MIURA

Students
Hitomi ACHIWA
Kyosuke WADA
Xiang SONG
Saki ONODERAMayu OZAKI

Research Summary
Mechanisms of Neural Network Formation: Neocorticaldevelopment and synapse formationtransient cell population that plays a crucial role as a “control
tower” during neocortical formation and also exerts effects on
adult cortical function.”

How does the mammalian neocortex acquire the unique sixlayered structure that is thought to be the structural basis forthe remarkable evolution of complex neural circuits? We focus
on subplate (SP) neurons that develop extremely early duringcortical development and disappear postnatally. Recently, we
found that SP neurons interact directly with young migratingneurons and play an essential role in radial neuronal migration.
Moreover, the SP layer is surrounded by a rich extracellularmatrix (ECM), suggesting that it may be an important signaling
center for mammalian corticogenesis. Functional studies of
the SP layer should lead to a better understanding of brain
development during evolution.
“We are interested in the roles of the subplate layer in thedevelopment of the cerebral cortex. Subplate neurons are a

Selected Publications
Ohtaka-Maruyama C (2020) “Subplate neurons as an organizer of mammalian

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

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

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

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

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

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

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

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

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

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

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

Reports, 28, 3144-3156.

31   

PROJECT / Brain & Neurosciences

Laboratory Head

Makoto HASHIMOTO

Makoto Hashimoto has been
the head of the Laboratory ofParkinson’s Disease since 2011.
He obtained his MD from the
University of Tokyo School of
Medicine in 1986, after which
he worked at the University ofTokyo Hospital until 1988. In
1992 he graduated from the
Graduate School of Medicine
at the University of Tokyo witha PhD in Biochemistry. He thenworked as a research associate
at the Salk Institute from 1992 to1995 and as a postdoctoral fellow
in the Dept of Neurosciences at
the University of California, San
Diego from 1995 to 2000. From2004 to 2011 he worked as a
deputy councilor researcher at
the Tokyo Metropolitan Institutefor Neuroscience before joining
the staff at TMIMS.

Parkinson's
DiseaseLaboratory HP: https://www.igakuken.or.jp/parkinson/

Staff
Researchers
Yoshiki TAKAMATSU

Research Assistants
Ryoko WADA

Research Summary
Our goal is to develop effective disease-modifying therapies forage-associated neurodegenerative diseases such as Alzheimer’s
disease (AD) and Parkinson’s disease (PD).

Alzheimers Dis. 2018, J. Parkinsons Dis. 2018). Further studiesof evolvability should contribute to the development of novel
therapy strategies for neurodegenerative diseases.

1. D e s p i t e e x t e n s i v e i n v e s t i g a t i o n , t h e p h y s i o l o g i c a lfunctions of amyloidogenic proteins (APs) associated withneurodegenerative diseases, including amyloid β for AD and
α-synuclein for PD, are currently unclear. We recently
proposed that APs may protect the brain from multiple
stressors through a heritable proteinaceous adaptation
mechanism we call evolvability (Fig.1) (Hashimoto M, et al. J.

2. We are also identifying small molecules that could be usefulfor the prevention of neurodegenerative diseases using
Drosophila molecular genetics (Fig. 2), cell biology, andtransgenic mice studies. Molecules identified in our study
may also be applicable to other diseases, including AD and
Huntington’s disease.

Fig 1. Evolvability and neurodegenerative disease:antagonistic pleiotropy of AP protofibrils

Fig. 2 Drosophila molecular genetics

Selected Publications
Takamatsu Y, et al. (2020) “Adiponectin Paradox as a therapeutic target of the cancer

Waragai M, et al. (2020) “Adiponectin Paradox as a Therapeutic Target Alzheimer's

evolvability in aging. ” Neoplasia. in press

Disease.” J Alzheimers Dis. 76(4):1249-1253.

Hashimoto M, et al. (2020) “Understanding Creutzfeldt-Jacob Disease from a Viewpoint

Waragai M, et al. (2020) “Adiponectin Paradox in Alzheimer's Disease; relevance toof Evolvability”. Prion. 14(1):1-8.

Amyloidgenic Evolvability? Front Endocrinol (Lausanne) :108. 101.

Ho G, et al. (2020) “Connecting Alzheimer's Disease with Diabetes Mellitus throughHashimoto M, et al. et al. (2019) “Possible Role of Amyloid Cross-Seeding in Evolvability

Amyloidogenic Evolvability Front Aging Neurosci.12:576192.

and Neurodegenerative Disease. J Parkinsons Dis. 9(4):793-802

Takamatsu Y, et al. (2020) “Amyloid Evolvability and Cancer. Trends Cancer. 6(8):624-627.

Takamatsu Y, et al. (2017) “Combined immunotherapy with “anti-insulin resistance”

Fujita M et al. (2020) “Possible Role of Amyloidgenic Evolvability in Dementia with Lewy
Bodies; Insights from Transgenic Mice Expressing P123H β-synuclein” Int J Mol Sci.
21(8):2849.

therapy as a novel therapeutic strategy against neurodegenerative diseases.” NPJ
Parkinson’s Disease 3: 4.
Takamatsu Y, et al. (2016) “Protection against neurodegenerative disease on Earth and inspace.” NPJ Microgravity 2: 16013.

   32

Schizophrenia patient-derived induced pluripotent stem cells. Blue, nuclei;
red and green, OCT4 and TRA-1-60 (pluripotent markers), respectively.

Psychiatry&
Behavioral
Sciences

PROJECT / Psychiatry & Behavioral Sciences

Project Leader

Makoto ARAI

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

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

Staff
Researchers
Masanari ITOKAWA
Yasue HORIUCHI
Mitsuhiro MIYASHITA
Kazuya TORIUMI
Hiroaki ISHIDA
Akane YOSHIKAWA
Kazuhiro SUZUKI
Yasuhiro MIYANO

Research Assistants
Ikuyo KITO
Nanako OBATA
Izumi NOHARA
Mai HATAKEYAMA
Chikako ISHIDA
Akiko KOBORI
Tomoko INOUE

Students
Tianran WANG
Riko AGARIE
Mai ASAKURA
Kyoka IINO
Azuna OZAWA
Chinatsu SUGIMURA
Yasufumi TOMITAMayuk MASADA

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   34

Son S, et al. (2020) “Enhanced carbonyl stress and disrupted white matter integrity inMiyashita M, et al. (2016) “The regulation of soluble receptor for AGEs contributes toschizophrenia.” Schizophr Res. S0920-9964(20)30435-7.

carbonyl stress in schizophrenia.” Biochem. Biophys. Res. Commun. 479: 447-452.

Mizutani R, et al. (2019) “Three-dimensional alteration of neurites in schizophrenia.” Transl

Miyashita M, et al. (2014) “Clinical Features of Schizophrenia With Enhanced Carbonyl

Psychiatry. 9: 85

Stress.” Schizophr. Bull. 40: 1040-1046.

Itokawa M, et al. (2018) ‘’Pyridoxamine: A novel treatment for schizophrenia with

Arai M, et al. (2010) “Enhanced Carbonyl Stress in a Subpopulation of Schizophrenia.”

enhanced carbonyl stress.’’ Psychiatry Clin. Neurosci. 72: 35-44.

Arch. Gen. Psychiatry. 67: 589-597.

Psychiatry & Behavioral Sciences / PROJECT

Project Leader

Yoshitaka TATEBAYASHI

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

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

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

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

Selected Publications

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

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

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

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

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

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

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

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

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

One 7: e33019.

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

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

11-21.

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

35   

PROJECT / Psychiatry & Behavioral Sciences

Project Leader

Makoto HONDA

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

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

Staff
Researchers
Taku MIYAGAWA
Akiyo NATSUBORI

Research Assistants
Takashi KOJIMA
Yasuko SEKI
Yoshiko HONDA
Visiting Scientist
Mihoko SHIMADA

Students
Momoka MIYAZAWA
Takuma OGAWA
Shun SUZUKI

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

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

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

Selected Publications   36

Natsubori A,et al (2020) “In vivo state-dependent dynamics of cellular energy status in

Shimada M, et al. (2018) “Epigenome-wide association study of DNA methylation incortical neurons”. Communications Biol 3 491

narcolepsy: an integrated genetic and epigenetic approach.” Sleep 41:zsy019

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

Toyoda H, et al. (2017) “Narcolepsy susceptibility gene CCR3 modulates sleep-waketype 1 patients. Sleep zsaa095.

patterns in mice.” PLoS ONE 12:e0187888

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

Miyagawa T, et al. (2013) “Effects of oral L- carnitine administration in narcolepsy

lateral hypothalamic brain and overlapping DNA methylation profiles between

patients: a randomized, double-blind, cross-over and placebo-controlled trial.” PLoS

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

ONE 8:e53707.

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

Miyagawa T, et al. (2011) “Abnormally low serum acylcarnitine levels in narcolepsy

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

patients.” Sleep 34:349-353.

Psychiatry & Behavioral Sciences / PROJECT

Project Leader

Kazutaka IKEDA

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

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

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

Research Assistants
Yoko HAGINO
Junko HASEGAWA
Etsuko KAMEGAYA
Yukiko MATSUSHIMA
Yuki SERITA
Yuko EBATA
Kyoko NAKAYAMA

Students
Yuiko IKEKUBO
Yukiko OCHIAI
Yoshihisa KATO
Aimi YAMAGISHI
Yoshihiko KOSAKIMoe SOEDA
Rie INOUE
Shoka MATSUYAMA

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
Fujita M, et al. (2020) “Increase in excitability of hippocampal neurons during novelty-

Ide S and Ikeda K. (2018) “Mechanisms of the antidepressant effects of ketamine

induced hyperlocomotion in dopamine-deficient mice.” Mol. Brain. 13: 126.

enantiomers and their metabolites. ” Biol. Psychiatry. 84:551-552.

Kotajima-Murakami H, et al. (2018) “Effects of rapamycin on social interaction deficits

Nishizawa D, et al. (2014) “Genome-wide association study identifies a potent locus

and gene expression in mice exposed to valproic acid in utero.” Mol. Brain 12:3

associated with human opioid sensitivity.” Mol. Psychiatry. 19: 55-62.

Sugaya N, et al. (2018) “A randomized controlled study of the effect of ifenprodil on

Sato A, et al. (2012) “Rapamycin reverses impaired social interaction in mouse models of

alcohol use in patients with alcohol dependence.” Neuropsychopharmacology Rep.

tuberous sclerosis complex” Nat. Commun. 3: 1292.

38(1):9-17.

37   

Laboratory / Psychiatry & Behavioral Sciences

Laboratory Head

Kanato YAMAGATA

Kanato Yamagata graduatedfrom Kanazawa University Schoolof Medicine and received M.D.
in 1985. He was engaged in the
research on the photoreceptorspecific protein at Cancer
Research Institute in Kanazawa
University as a graduate
student. After receipt of Ph.D. in
1989, he moved to the Johns
Hopkins University and started
to work on “activity-regulated
gene expression in the brain”
under the supervision of Prof.
Daniel Nathans. After comingback to Japan, he continued toinvestigate the roles of thesegene products in synaptic
plasticity and has clarified mostgene products are involved in
the pathogenesis of various
brain diseases. His current
interest is a development of new
therapeutics for developmental
disorders accompanied
intellectual disability and autism.

Synaptic
Plasticity
Laboratory HP: https://www.igakuken.or.jp/plasticity/

Staff
Researchers
Tadayuki SHIMADA
Chihiro HISATSUNE
Hiroko SUGIURA
Keiko MORIYA-ITO

Research Assistants
Fumie MASUDA
Tomoko KAWANO

Students
Hirono KOBAYASHI
Yuka KAWAMOTO
Shiho SAKAI

Research Summary
We study the molecular basis of activity-dependent synaptic
plasticity. In particular, we have cloned a set of immediate earlygenes (IEGs) that are rapidly transcribed in neurons involved
in information processing, and that are essential for long term
memory. IEG proteins can directly modify synapses and provide
insight into cellular mechanisms that support synaptic plasticity.
Furthermore, these IEG products have been shown to be
involved in developmental brain disorders, including refractory
epilepsy, intellectual disability and/or autism.

cellular and neural network basis of behavioral plasticity.
We are also exploring the possibility that these IEG products
could be therapeutic targets for developmental disorders. We
are making genetic mouse models of developmental disorders
and are testing the effects of several drug inhibitors against IEGs.

For example, COX-2 and mPGES-1 are prostaglandin synthasesthat exacerbate neuronal cell death after seizures, leading to
intractable epilepsy. Arcadlin is a protocadherin that induces
spine shrinkages after seizures, resulting in developmental
delay or amnesia. Rheb regulates excitatory synapse formation
via syntenin. Constitutive activation of Rheb causes TSC(tuberous sclerosis complex), which is accompanied by epilepsy,
mental retardation and autism. Finally, neuritin is a secreted or
membrane-anchored protein and induces neurite branching.
It may be involved in temporal lobe epilepsy. Thus, analysisof rapid de novo transcription provides novel insights into theSelected Publications
Takeuchi C, et al. (2020) “Dendritic Spine Density is Increased in Arcadlin-deleted Mouse
Hippocampus.” Neuroscience 442:296-310.
Shimada T, et al. (2019) “Syntenin: PDZ Protein Regulating Signaling Pathways andCellular Functions “ Int. J. Mol. Sci. 20(17):4171.
Shimada T and Yamagata K. (2018) 442:296-310. “Pentylenetetrazole-Induced Kindling
Mouse Model.” JoVE (136).
Shimada T, et al. (2016) “Neuritin Mediates Activity-Dependent Axonal Branch Formation   38

in Part via FGF Signaling.” J. Neurosci. 36(16):4534-4548.
Sugiura H, et al. (2015) “Rheb activation disrupts spine synapse formation throughaccumulation of syntenin in tuberous sclerosis complex.” Nat. Commun. 6:6842.
Masui K, et al. (2015) “Glucose-dependent acetylation of Rictor promotes targetedcancer therapy resistance.” Proc. Natl. Acad. Sci. USA 112(30):9406-9411.
Yasuda S, et al. (2014) “Activation of Rheb, but not of mTORC1, impairs spine synapse
morphogenesis in tuberous sclerosis complex.” Sci. Rep. 4:5155.

Psychiatry & Behavioral Sciences / Laboratory

Laboratory Head

Haruo OKADO

Haruo Okado, the laboratory
head of Neural Development
Laboratory. After graduation frommedical school of University ofTokyo in 1986, he conducted
developmental biology using
ascidian embryos under Dr.
Kunitaro Takahashi at Brain
institute of Univ. of Tokyo as a
graduate student, and received
Ph.D in 1991. After abroad study
about regulatory expression of
glutamate receptors under Dr.
Stephan Heinemann in the Salk
Biological Institute, he has beenworking how brain is developing
and function using mice in theTokyo metropolitan institute forneurosciences, and from 2011 in
Tokyo metropolitan institute of
medical science. In particular,
he focus on the function of thetranscription repressor RP58 on
brain development and function.
In recent, he and colleagues areinterested in the interaction ofgenetic factor and environmental
factor in the development of thebrain.

NeuralDevelopment
Laboratory HP: https://www.igakuken.or.jp/differentiation/

Staff
Researchers
Shinobu HIRAITomoko TANAKA

Research Assistants
Katsuko TAKASAWA
Hiroko SHIMBO
Fumika KAWANO

Research Summary
Various factors control differentiation of neural stem cells
and survival of the resulting neurons, and aberrancy in theseprocesses are associated with intellectual disability, agerelated brain disorders, and brain tumors. We aim to elucidate
the mechanisms of development and maintenance of brain
functions, ultimately to develop methods for the prevention andtreatment of intractable cranial nerve diseases.

Our major projects include
1. Understanding how the transcriptional repressor, RP58,
regulates brain development and maintenance. From several
findings, I propose three hypotheses: first, artificial or evolutional
regulation of RP58 regulation can increases neurons in number
by promoting the formation of the outer SVZ. Second, a decreasein RP58 expression in aging contributes to brain dysfunction in
aging. Third, the quantity of RP58 is involved in the recognition
function and development of glioma, and artificial regulation of
RP58 can control and useful treatment for cognitive dysfunction
and glioma.

2. Altering the nutritional environmental factors to manipulate
brain development and functions. We demonstrate that a highsucrose diet during adolescence induces psychosis-related
phenotypes, such as hyperactivity, poor working memory,
impaired sensory gating, and disrupted interneuron function,
particularly in mice deficient for glyoxalase-1, an enzyme
involved in detoxification of sucrose metabolites. Further, thehigh-sucrose diet induced microcapillary impairment andreduced brain glucose uptake. We proposed that psychiatricdisorders are associated with microvascular brain damage,possibly due to various environmental stresses including
metabolic stress.
3. Understanding the roles of environmental factors indevelopment and aging of brain functions. We establishedthat postnatal maternal separation facilitates the impairmentof spatial cognitive function and the formation of amyloid beta
plaque in Alzheimer’s disease (AD) model mice, with disruption of
micro-capillaries, and we verified that early-life stress constitutes
a risk factor for AD. Furthermore, we found that morphologicaland functional changes to microglia are early symptoms in our
experimental model, and suggest the possibility that impairmentof the cerebral vascular system caused by interactions between
microglia and vasculature induces dysfunction in the BBB,
thereby facilitating the clinical condition of AD.

Selected Publications
Okado H (2019) Regulation of brain development and brain function by thetranscriptional repressor RP58. Brain Res. 1705:15-23.
Hirai S, et al. (2018) “Developmental Roles and Evolutionary Significance of AMPA-Type
Glutamate Receptors.” BioEssays. 2018 2018 Sep;40(9):e1800028.
Hirai S, et al. (2017) “AMPA glutamate receptors are required for sensory-organ formationand morphogenesis in the basal chordate.” Proc. Natl. Acad. Sci. USA. 114: 3939-3944.
Nakajima K, et al. (2015) “Benzodiazepines induce sequelae in immature mice with
inflammation-induced status epilepticus.” Epilepsy & Behavior 52: 180-186.
Ohtaka-Maruyama C, et al. (2013) “RP58 regulates the multipolar-bipolar transition of

newborn neurons in the developing cerebral cortex.” Cell Rep. 3: 458-471.
Hirai S, et al. (2012) “RP58 controls neuron and astrocyte differentiation by
downregulating the expression of Id1-4 genes in the developing cortex.” EMBO J. 31:
1190-1202.
Ohtaka-Maruyama C, et al. (2012) “The 5’-flanking region of the RP58 coding sequenceshows prominent promoter activity in multipolar cells in the sub- ventricular zone duringcorticogenesis.” Neuroscience 201: 67-84.
Okado H, et al. (2009) “Transcriptional repressor RP58 is crucial for cell-division
patterning and neuronal survival in the developing cortex.” Dev. Biol. 331: 140-151.

39   

Laboratory / Psychiatry & Behavioral Sciences

Laboratory Head

Shinji KAKEI

Dr. Kakei graduated from Tokyo
Medical and Dental University,
School of Medicine, to receive
M.D. degree in 1986. Then,he moved on to the Ph.D.
course to make physiologic
and morphologic studiesof the cerebro-cerebellar
communication loop at a singlecell level under the supervision ofProf. Yoshikazu Shinoda. In 1996,
he moved to the United States
to be a postdoc in the laboratoryof Prof. Peter L. Strick at State
University of New York. There, hedesigned a novel experimental
paradigm to dissociate intrinsic(i.e., muscle and joint) andextrinsic (i.e., spatial) coordinate
frames for neuron activities
in behaving monkeys. They
published a series of influential
papers that outlined sensorimotortransformation in cortical motor
areas (Kakei et al. Science, 1999;
Nat Neurosci, 2001, Neurosci Res
2003). After returning to Japan,
he first set up his lab at Tohoku
University to study information
processing in the cerebrocerebellar communication
loops. More recently, he is trying
to integrate neuron recording
studies in animals and movement
analysis in patients withneurological disorders aiming at
a synergistic effect.

Movement
DisordersLaboratory HP: https://www.igakuken.or.jp/motor-control/

Staff
Researchers
Kyuengbo MIN
Takahiro ISHIKAWA
Takeru HONDA

Students
Masaya WATANABE

Research Summary
We try to understand how the brain controls our movementsin the real world. We study the process of action generation ata single neuron level using animal models to understand how
movements are processed in the brain. We also study actionsof healthy people, as well as those with neurological disorders,such as cerebellar disorders, Parkinson’s disease, or strokes. We
look for building-blocks of motor control with multidisciplinary
approaches. Our tools include various neurophysiologicalrecording techniques (single unit recording, electromyography(EMG) and electro-encephalography (EEG)), brain stimulation,neuroimaging, analysis of movement kinematics and a largescale modeling. We have two long-term goals: 1) to understandthe basic function of the motor structures of the brain including
the cerebellum, the basal ganglia, and the motor cortex; and 2) tounderstand how our brain controls our movements on the basisof the findings in 1).
This figure summarizes our cutting edge finding that the cerebellum function as a
Kalman filter. MF: mossy fiber (red), PC: Purkinje cell (green), DC: dentate cell (lightblue). Granule cells (orange) and inhibitory interneurons (blue) are included to show thebasic structure of the cerebellar neuron circuitry. Three stages of linear computation: (A)Predictive step, (B) Filtering step, (C) Internal model prediction, are accompanied withthe three types of computation of Kalman filter.
(Tanaka, Ishikawa and Kakei Cerebellum 2019).

Selected Publications
Tanaka H, et al. (2020) “The Cerebro-Cerebellum as a Locus of Forward Model: A

Tomatsu S, et al. (2016) “Information processing in the hemisphere of the cerebellar

Review.” Front Syst Neurosci. 14:19. doi:10.3389/fnsys.2020.00019.

cortrexfor motor control of wrist movement.” J. Neurophysiol. 115:255-270.

Honda et al. (2020) “Assessment and rating of motor cerebellar ataxias with the Kinect

Ishikawa T, et al. (2016) “The cerebro-cerebellum:Could it be loci of forwardmodels?”v2 depth sensor: Extending our appraisal.” Front Neurol. 2020 11:179. doi: 10.3389/

Neurosci. Res. 104:72-79.

fneur.2020.00179.
Kakei S, et al. (2019) “Contribution of the Cerebellum to Predictive Motor Control and Its
Evaluation in Ataxic Patients.” Front Hum Neurosci. 13:216.
Tanaka H, et al. (2019) "Neural Evidence of the Cerebellum as a State Predictor.”
Cerebellum. 18(3):349-371.

   40

Lee J, et al. (2015) “A new method for functionalevaluation of motor commands
inpatients with cerebellar ataxia.” PLoS One 10:e0132983.
Ishikawa T, et al. (2014) “Releasing dentatenucleus cells from Purkinje cellinhibition
generates outputs fromthe cerebrocerebellum.” PLoS One 9:e108774 (pp.1-16).

A particle structure model of Enterovirus 71 generated from the Protein Data Base
4AED. Red and green indicate surface and interior compartments, respectively.

Diseases&
Infection

PROJECT / Diseases & Infection

Project Leader

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

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

Staff
Researchers
Michinori KOHARA
Tsubasa MUNAKATA
Daisuke YAMANE
Kenzaburo YAMAJI

Yuko TOKUNAGA
Naoki YAMAMOTO
Takahiro SANADA
Yusuke MATSUMOTO
Tomoko HONDA

Research Assistants
Asako TAKAGI
Risa KONO
Masahiko HIGA

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
Saito M, et al. In Press “Targeted macrocycles hamper hemagglutinin adsorption andfusion, and have antiviral effects in murine and macaque models of influenza.” Nat
Commun.
Sanada T, et al. (2019) “Avian H5N1 influenza virus infection causes severe pneumonia in
the Northern tree shrew (Tupaia belangeri).” Virology 529:101-110.
Tokunaga Y, et al. (2017) “Selective inhibitor of Wnt/-catenin/CBP signaling ameliorates
hepatitis C virus-induced liver fibrosis in mouse model.” Sci. Rep. 7: 325.
Sanada T, et al. (2016) “Transmission of HBV DNA mediated by ceramidetriggered   42

extracellular vesicles.” Cell Mol. Gastroenterol Hepatol. 3:272-283.
Yasui F, et al. (2016) “Sensitization with vaccinia virus encoding H5N1 hemagglutinin
restores immune potential against H5N1 influenza against H5N1 influenza virus.” Sci. Rep.
6: 37915.
Sanada T, et al. (2016) “Property of hepatitis B virus replication in Tupaia belangeri
hepatocytes.” Biochem. Biophys Res. Commun. 469: 229-235.
Yamamoto N, et al. (2016) “Novel pH-sensitive multifunctional envelopetype nanodevice
for siRNA-based treatments for chronic HBV infection.” J. Hepatol. 64: 547-555

Diseases & Infection / PROJECT

Project Leader

Satoshi KOIKE

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

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

Staff
Researchers
Kyousuke KOBAYASHI
Naoki KAJIWARA

Research Assistants
Ayako TAKASHINO
Masako UKAJI
Namiko NOMURATomoha NISHIZAWA
Wakako MIWATASHI
Minori ISHIDA
Sayaka ESAKI

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

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

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

initiation of uncoating.

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

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

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

Its Receptor Attachment and Resistance to Neutralizing Antibody during Cynomolgus

Pathog., 18:16(3)e1008428

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

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

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

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

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

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

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

Attachment Receptor Usage and Neurovirulence in Human Scavenger Receptor B2

71.” Nature Medicine 15:789-801

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

43   

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
Researchers
Kazuhiko NAMEKATA
Xiaoli GUO
Atsuko KIMURA
Chikako HARADA
Takahiko NORO

Euido NISHIJIMA
Yuta KITAMURA
Naoki KIYOTA

Research Assistants
Mayumi KUNITOMO
Students
Kaori SEGURA

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

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

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.
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 an animal model of multiple sclerosis(MS). Thus, DOCK10 may be a novel therapeutic target for diseases such as MS and optic
neuritis.
Finally, we have been studying the relationship between glaucoma and EAAT1, aglutamate transporter that regulates glutamate signaling. Glutamate is the major excitatoryneurotransmitter in the central nervous system and we identified EAAT1 variants that areassociated with glaucoma. These loss-of-function variants may contribute to pathogenesisof glaucoma.

Selected Publications
Namekata, K., Guo, X., Kimura, A., Azuchi, Y., Kitamura, Y., Harada, C. and Harada, T.

Kimura, A., Noro, T. and Harada, T. Role of animal models in glaucoma research. Neural

Roles of the DOCK-D family proteins in a mouse model of neuroinflammation. Journal ofRegeneration Research 15(7), 1257-1258, 2020.

Biological Chemistry 295(19), 6710-6720, 2020.

   44

Yanagisawa, M., Namekata, K., Aida, T., Katou, S., Takeda, T., Harada, T., Fuse, N., theNishijima, E., Namekata, K., Kimura, A., Guo, X., Harada, C., Noro, T., Nakano, T. and

Glaucoma Gene Research Group, and Tanaka, K. EAAT1 variants associated with

Harada, T. Topical ripasudil stimulates neuroprotection and axon regeneration in adultglaucoma. Biochemical and Biophysical Research Communications 529(4), 943-949,

mice following optic nerve injury. Scientific Reports 10(1), 15709, 2020.

2020.

Harada, C., Noro, T., Kimura, A., Guo, X., Namekata, K., Nakano, T. and Harada, T.

Kikuchi, K., Dong, Z., Shinmei, Y., Murata, M., Kanda, A., Noda, K., Harada, T. and Ishida,

Suppression of oxidative stress as potential therapeutic approach for normal tension

S. Cytoprotective effect of astaxanthin in a model of normal intraocular pressureglaucoma. Antioxidants 9(9), 874, 2020.

glaucoma. Journal of Ophthalmology 2020, 9539681, 2020.

Diseases & Infection / PROJECT

Project Leader

Kazunori SANGO

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

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

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

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

Students
Yosuke NAGAI
Masaki OBA
Nozomi SAKATA

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
Mizukami H, et al. “Role of glucosamine in development of diabetic neuropathy

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

independent of aldose reductase pathway.” Brain Commun, Oct 9, 2020 (on line).

neuron-like cell line NSC-34 and an adult rat Schwann cell line IFRS1.” Histochem. Cell

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

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

Niimi N, et al. (2018) “A spontaneously immortalized Schwann cell line from aldose

Cell Biol. 153:111-119.

reductase-deficient mice as a useful tool for studying polyol pathway and aldehyde

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

metabolism.” J. Neurochem. 144:710-722.

-synuclein chaperone. ” Brain 142:2845-2859.

Sango K, et al. (2017) “Impaired axonal regeneration in diabetes. Perspective on the*Nakamura S, *Oba M, et al. (2019) “Suppression of autophagic activity by Rubicon is asignature of aging.” Nat. Commun. 10:847. (*co-first authors)underlying mechanism from in vivo and in vitro experimental studies.” Front. Endocrinol.
8:12.

45   

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

Research Assistants
Szuyin HSU

Students
Daiki KONDO
Ittetsu NAKAJIMA
Terumi ONO
Anri SAITOH
Minato MAEDA

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

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

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

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

Miyaoka Y, et al. (2016) “Using Digital Polymerase Chain Reaction to Detect Single-(CRISPR)/CRISPR-associated protein 9 with improved proof-reading enhances

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

homology-directed repair.” Nucleic Acids Res. 46: 4677-4688.

2016:688-692.

Miyaoka Y, et al. (2018) “Detection and Quantification of HDR and NHEJ Induced byMiyaoka Y, et al. (2016) “Systematic quantification of HDR and NHEJ reveals effects ofGenome Editing at Endogenous Gene Loci Using Droplet Digital PCR.” Methods Mol.

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

Biol. 1768: 349-362.
Workman MJ, et al. (2017) “Engineered human pluripotent-stem-cell-derived intestinal
tissues with a functional enteric nervous system.” Nat. Med. 23: 49-59.

   46

Miyaoka Y, et al. (2014) “Isolation of single-base genome-edited human iPS cells without
antibiotic selection.” Nat. Methods 11: 291-293.

Diseases & Infection / PROJECT

Laboratory HeadTakachika HIROI

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

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

Staff
Researchers
Mayumi SAEKI
Masanobu WATANABE
Tomoe NISHIMURA

Research Assistants
Noriko KITAMURA

Students
Eriko ANDO
Kohei FUSANO
Satoshi UNO

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

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

Selected Publications
Tachibana M, et al. (2020). “Ablation of IL-17A leads to severe colitis in IL-10-deficient
mice: implications of myeloid-derived suppressor cells and NO production.” Int Immunol.
32: 187-201.
Kitamura N, et al (2020). “Identification of novel interacting regions involving calcineurin
and nuclear factor of activated T cells.” FASEB J. 34: 3197-3208.
Takaiwa, F, et al. (2019). “Development of rice-seed-based oral allergy vaccines

immunotherapy.” J Agric Food Chem. 67: 13127-13138.
Kaminuma O, et al. (2018). “Downregulation of NFAT3 due to lack of T-box transcription
factor TBX5 is crucial for cytokine expression in T cells.” J Immunol. 200: 92-100.
Yokoyama S, et al. (2009) “Antibody-mediated blockade of IL-15 signaling reverses
autoimmune intestinal damage in a mouse model of celiac disease.” Proc. Natl. Acad.
Sci. USA 106: 15849-15854.

containing 2 hypoallergenic Japanese cedar pollen allergen derivatives for47   ResearchCenters

Genome & Medical Sciences / Research Center

Vice Director

Hideya KAWAJI

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

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

Staff
Director
Hisao MASAI
Senior Researcher
Keisuke OBOKI

Researcher
Naoko YOSHIZAWA
Yuichiro HARA
Saki SAITO
Naoki HIROSE

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

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

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

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

Takamochi,K., et al. (2016) "Novel biomarkers that assist in accurate discrimination ofhuman transcribed cis-regulatory elements." Nat Genet. 51(9):1369-1379.

squamous cell carcinoma from adenocarcinoma of the lung." BMC Cancer 16, 760.

Yoshida T, et al. (2019) "Evaluation of off-target effects of gapmer antisense

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

oligonucleotides using human cells. "Genes Cells. 24(12):827-835.

clonally amplified and single-molecule next-generation sequencing." Genome Res. 24,

Yoshida, E., et al. (2017) "Promoter-level transcriptome in primary lesions of endometrial
cancer identified biomarkers associated with lymph node metastasis." Sci. Rep. 7, 14160

708–717.
Forrest, A.R.R., Kawaji,H., et al. (2014) "A promoter-level mammalian expression atlas.
Nature, 507, 462–70.

49   

Research Center / Genome & Medical Sciences

Director Unit Leader

Atsushi NISHIDA

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

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

Staff
Researcher
Syudo YAMASAKI

Researcher
Miharu NAKANISHI

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

Teen Cohort is a project that

We are promoting the participation

We have developed a care program

scientifically examines how toof people with mental illnesses

to support people with dementia,

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

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

all municipalities in Tokyo.

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

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

residential care settings.” J Alzheimer's Dis.
Yamasaki S, et al. (2020) “Interaction of adolescent aspirations and self-control on
wellbeing in old age: Evidence from a six-decade longitudinal UK birth cohort.” J Positive
Psychol.
Yamasaki S, et al. (2019) “Maternal diabetes in early pregnancy, and psychotic   50

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

Social Science & Medicine Sciences / Unit

Unit Leader

Yuki NAKAYAMA

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

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

Staff
Researchers
Michiko HARAGUCHI
Chiharu MATSUDA
Akiko OGURA
Yumi ITAGAKI
Yasuyo KASAHARA

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

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

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

Selected Publications
Nakayama Y, Shimizu T, Matsuda C, Haraguchi M, et al. (2019) “Body weight variation
predicts disease progression after invasive ventilation in amyotrophic lateral sclerosis.”
Scientific Reports volume 9, Article number: 12262
Shimizu T, Nakayama Y, Matsuda C, Haraguchi M, et al. (2019) “Prognostic significance ofbody weight variation after diagnosis in ALS: a single-centre prospective cohort study.”
Journal of Neurology .266(6), 1412–1420
Matsuda C, Shimizu T, Nakayama Y, Haraguchi M. (2019) “Cough peak flow decline rate
predicts survival in patients with amyotorophic lateral sclerosis” Muscle & Nerve. 59(2)168-173.
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

51   

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.

53   

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.
•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.

   54

Research Support

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

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

Takayuki HARADA
We facilitate collaboration between basic scientists at research
institutes and medical doctors at hospitals. We have a supporting
budget of 500,000 yen for collaborative clinical studies withmedical doctors at Tokyo Metropolitan Hospitals.

Conference with researchers and medical doctors

We manage ethical issues related to human specimens and we
provide specialized support for bringing knowledge and findings
from basic scientific research to development of new therapy inhumans.

A young scientist discussing with medical Conference withresearchers and medical doctors doctors in conference55   Research Support

Neuropathology
Laboratory HP: https://pathologycenter.jp/english/en_index.html

Translational Researchusing human materials andManagement of Database for
Essential Brain Anatomy &Neuropathology

Staff
Erika SEKI
Rika KOJIMA
Kazunari SEKIYAMANobuko UEKI
Keiko AKAMATSU
Tomoko YAGI
Hiromi EGUCHI
Tsunemi YAMANISHI Yoshitomo UMITSU

Laboratory Head

Nobutaka ARAI
The Laboratory of Neuropathology has more than 5,000 setsof human autopsied brain slides with a wide variety of humanneurological diseases. In recent years, we have been scanning   56

these slides with virtual slide instruments. Using this digital dataand its derivatives, we are constructing a digital neuropathology
library.

Public Relations
andOther Activities

TMIMS Programs
Public lectures
Each year we present 8 pubic lectures toinform the public of our research progressand enlighten people on various medical
issues pertinent to their health andwelfare. In 2020, we had to cancel threelectures due to the pandemic, but we
had five, including three online. Lecture
topics included adolescent mental care,
addiction, hearing loss, Parkinson’s
disease, and memory.

How can you prevent and recover from addictive disorders?
...................Kazutaka IKEDA (TMIMS, Addictive Substance Project)...................Toshihiko MATUMOTO (NCNP)
How wil mind development during adolescence affect healthy mental state in laterstage of life?
...................Atsushi NISHIDA(TMIMS, Mental Health Promotion Project)...................Kiyoto KASAI (The University of Tokyo Hospital)
How can you prevent and cure hearing loss?
...................Yoshiaki KIKKAWA(TMIMS, Mammalian Genetics Project)...................Masato FUJIOKA (Keio University)
Parkinson's diseases: what we know now from the latest basic and clinical studies...................Noriyuki MATSUDA (TMIMS, Ubiquitin Project)...................Taku HATANO (Juntendo University)
Can you create memory?
...................Kaoru INOKUCHI (University of Toyama)

Science café
In the past ten years we have had 32
special science presentations geared
toward the general public. These “sciencecafes” provide people of all ages with theopportunities to learn, experience, andenjoy science first hand in a casual setting.
In 2020, we had three online science cafes
on topics such as “what is PCR?”, “what doyou need to know about virus infections?”
and “how does the human brain develop
and how is it different from brains of otherspecies?” The participants enjoyed ouronline quizzes in these events.

   58

PCR: how it works and how it was discovered.
...................................................Yuichiro MIYAOKA(TMIMS, Regenerative Medicine Project)
Virus infection: PCR, antigen test and antibody test...................................................Satoshi KOIKE(TMIMS, Neurovirology Project)
Brain: mechanisms of its formation and evolution...................................................Chiaki OHTAKA-MARUYAMA(TMIMS, Neural Network Project)Institutional seminars (Igakuken Seminars)
We have institutional seminars on a regular basis. In 2020, despite the coronavirus pandemic
we had 17 seminars, 10 at the institute and 7 online, by both domestic and international
scientists including those from the Sorbonne, France, and Texas, USA.

Development of intergration-dependent genetic switch-on systems................Takuma KUMAMOTO (Sorbonne Université)

Cryo EM analyses of the TOM complex, the gateway to mitochondria................Yuhei ARAISO (Kanazawa University)

Roles of olfactory cortex as information-processing hub................Hiroyuki MANABE (Doshisha University)

Chemical genetic analyses of spacial molecular network profiling of tripoint synaps................Tetsuya TAKANO (Keio University)

Analyses of morphological phenotypes of mice by X-ray imaging................Masaru TAMURA (RIKEN)
Mechanisms of mammalian hibernation; syrian hamster as a model................Yoshifumi YAMAGUCHI (Hokkaido University)
The Schedule for the evaluating of the individual Quality of Life-direct
weighting: SEIQoL-DW................Yoshihiko SAKASHITA (Chiba Cancer Center)................Akira YAMAMOTO (R102 Co.,Ltd.)
Development of versatile softwares for novel genome editing systems................Hideto MORI (The University of Tokyo)
Rapid induced protein degradation by an improved Auxin-degron system
and its application for the studies of genome maintenance mechanisms................Masato KANEMAKI (NIG)
Who kills science?
................Momoko SUDA (The Mainichi Newspapers)

Circadian quartz and clock aging................Hikari YOSHITANE (The University of Tokyo)
Comprehensive analyses of antibody/ T cell receptor by high-speed one
cell analyses................Hidetaka TANNO(The University of Texas at Austin)
Ghost cytometry technologies and beyond................Sadao OTA (The University of Tokyo)
Genetic tracing of formation of cerebral cortex functional area................Takayoshi INOUE (NCNP)
Translational research by MRI brain imaging of small animals................Tomokazu TSURUGIZAWA (AIST)
Somatic cell nuclear transfer by micromanipulator and its application................Eiji MIZUTANI (University of Tsukuba)

Knowing the biochemical microbrain for memory................Yukinori HIRANO (Kyoto University)

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

online lectures, including one delivered by Yuichiro Miyaoka on
regenerative medicine and gene editing, and the other by Takeru
Honda on braininfunctions.

Joint programs with universities
Many scientists at TMIMS have joint appointments as visiting professors or lecturers at various
universities. Unfortunately, this year we had to cancel our annual “open institute” events forprospective graduate students due to the coronavirus pandemic, but we currently have 152
students from affiliated universities and other schools, who conduct their research here.

Support for students and young scientists
Research Associate Fellowships
We provide graduate students who conduct their masters/
Ph.D. research at TMIMS with research associate fellowshipsthat provide them with financial support, and allow them toconcentrate on their studies and research.

Travel support for young scientists attending
international meetings
We provide students and young scientists at TMIMS with travel
fellowships to attend international meetings where they can present
their results and meet other students and scientists in their fields.
59   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, 2021