Summary of Proposal
Host institution
Chief entire-project
officer(Head of host institution)
Chief center-project
officer

Masashi Yanagisawa, Center for Behavioral Molecular Genetics, Professor andDirector

Center director

Masashi Yanagisawa, Center for Behavioral Molecular Genetics, Professor andDirector

Center nameInternational Institute for Integrative Sleep Medicine

Project Summary

Mission statement
and/or Center identity

Target research fieldResearch objectives

Outline of management

University of Tsukuba
Nobuhiro Yamada, President

Sleep is a remarkably universal phenomenon in the higher animal species, and its
disturbances reduce mental and physical wellbeing. However, the function of sleep andthe mechanism for sleep regulation still remain unknown; these questions are among themost important challenges in modern neuroscience. The proposed research center will
gather the world prominent scientists from multiple research fields contributing to theneurobiology of sleep. We will aim at elucidating the fundamental mechanism of
sleep/wake regulation by combining the cutting-edge methodologies of neurobiology,
molecular genetics and physiology. We will induce the fusion of medicine, chemistry,
pharmacology and biology in order to reveal the pathophysiology of sleep disorders andrelated diseases, and to develop methods for their treatment and prevention. Throughthese research efforts, we will strive to reduce sleep disorders and associated diseases,
and to contribute to an improvement of physical and mental health in today’s aging
society with a dwindling birthrate.
The mission of this WPI Center is to be a multidisciplinary, international hub for the
research to elucidate the fundamental mechanism of sleep/wakefulness, to develop
strategies to regulate sleep, and to contribute to enhancement of world health throughthe combat with sleep disorders and associated diseases.
Name of the target research field Sleep biomedicine
Sleep biomedicine, as defined here, is an inherently interdisciplinary field in terms of
methodology, spanning molecular genetics, cellular biology, neurophysiology, neurochemistry,
pharmaceutical sciences, medicinal chemistry, and clinical and social medicine. While focusing on
sleep, the field is also interdisciplinary with respect to its integral research targets, e.g., studying
mood disorders as well as metabolic diseases that are closely associated with pathologicalvariations in sleep/wake states.
Importance of the target research field
Sleep is a behavior that everyone experiences daily and it takes up as much as one third of one’s
entire lifetime. While sleep has been a black box stubbornly resisting scientists’ challenges, its
medical and social importance is very clear. Healthy sleep is necessary for maintaining our mind
and body fitness; lack of sound sleep not only causes a reduction in higher brain functions including
memory and decision making, but also increase the risk of mood disorders such as depression. The
society demands the development of strategies to remedy sleep disorders and associateddiseases.
Research trend of this field
As for the current trend of the field, triggered by the reports by Yanagisawa that a deficiency ofthe hypothalamic neuropeptide OREXIN is the root cause of the then-mysterious sleep disorder
NARCOLEPSY, a consensus has been formed by most researchers in the field that orexin
constitutes one of the centerpieces of the neural circuitry regulating sleep and wakefulness.
Moreover, multiple pharmaceutical companies are currently focused on developing new classes of
sleeping pills, indicating the consensus among the domestic and overseas pharmaceuticalindustries that this field is highly important for drug discovery.
Reasons why the project fit for this call for proposals
Japan has been producing a number of researchers who have made significant
accomplishments in the field of sleep biomedicine. Masashi Yanagisawa and Takeshi Sakurai
discovered the neuropeptide orexin and unraveled pathophysiological mechanisms of narcolepsy.
This is arguably one of the most significant discoveries in the past 50 years of sleep research, which
has created a new avenue of inquiry in the field: the two papers describing the discovery of orexin
and the narcolepsy phenotype in orexin knockout mice have been cited more than 4,400 times
combined. While primarily focusing on sleep, they have been conducting various behavioral studies
that are related to sleep. Hiromasa Funato and Yanagisawa elucidated the potent role of orexin inbasal metabolism and body weight regulation, uncovering the possibility of drug discovery formetabolic diseases. In part due to the wide recognition of these contributions, Yanagisawa has
been selected as one of the Principal Investigators for the FIRST Program of the Cabinet Office ofJapan, which has allowed him to intensively promote sleep research at his new Center hosted by
the University of Tsukuba.
The research objectives that the proposed center seeks to achieve are: 1) elucidation of thefundamental mechanisms of sleep/wake, 2) elucidation of molecular pathogenesis of sleep
disorders and related diseases, and 3) development of treatments for sleep disorders.
Establish a top-down administrative system headed by the Center Director by fully utilizing his
long-term experience at an American university.
Under the supervision of the Administrative Director who is thoroughly knowledgeable in both
the research contents of the center and the administrative affairs of the national university
corporation, the administrative staff will be composed of the Administrative Director, Assistant
Administrative Director, and the following three sections. (General affairs section, Accounting
section, Research fund section).

（Host institution：University of Tsukuba

Center name：International Institute for Integrative Sleep Medicine）

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Researchers and othercenter staffs, satellites,
partner institutions
Administrative director

Outline of research
environment

Outline of indicators forevaluating a center’s
global standing

Securing researchfunding

Decision-making system
In order to facilitate efficient and flexible administration of the research center, the Center
Director will have the sole authority of decision-making related to the personnel and management
matters within the Center, except for the removal of himself and the determination of his own salary.
Regardless of the position, anyone who is participating in this Center can offer his/her opinions
regarding the management or treatment directly to the Center Director.
Allocation of authority between the center director and host institution
The President of the University has the authority to elect or dismiss the Center Director, The
Center Director has a wide range of authorities regarding the general management and internal
administration of the research center.
Principal Investigators: 15 (foreigners 5) (Achieved by October, 2013), Total Researchers: 115(foreigners 35) (Achieved by March, 2015), Total Staff at Core-Center: 169 (Achieved by March,2015), Main principal investigators: Masashi Yanagisawa, Hiromasa Funato, Takeshi Sakurai,
Yoshihiro Urade, Robert Greene, Qinghua Liu, Hiroshi Nagase, Ichiyo Matsuzaki, Hitoshi Shimano,
Junichi Hayashi, Akiyoshi Fukamizu, Satoru Takahashi, Tetsuo Shimizu, Carla Green, Joseph
Takahashi, Satellite: University of Texas Southwestern Medical Center, Akita University,
Collaboration: RIKEN BioResource Center

Katsutoshi Goto, Professor Emeritus, University of Tsukuba(1) Establish a strong supportive organization in order to decrease the burden of administrative
obligations of scientists so that they concentrate on their research. (2) Reduce the burden of
administrative obligations of researchers and allow them to devote themselves exclusively to theirresearch. (3) Take advantage of Tsukuba as a research city in providing living support for
researchers. (4) Provide a sufficient amount of startup research funding and strong administrative
support when applying for external funding through the entire application process for the
independent researchers. (5)Conduct International recruitment to hire post-doctoral fellows. (6)English will be used as an official language at the research center. (7) Adopt a system for evaluating
research and merit-based compensation. (8) Provide appropriate equipment and facilities, office
and animal center (space exceeding 5000m2) as a top world-premier research center. (9) Holdinternational symposia once a year, and invited seminar series twice a month. And hold a retreat
once a year for the development of students and young researchers, promotion of collaborative
researches, and also an increased sense of a family-like unity of the Center. Provide workshops atoverseas Satellites to increase the visibility of the research center overseas.
i) Criteria and methods to be used for evaluating the center’s global standing in the subject field
1. Number of citations of published papers in the medium to long term. 2. Positions and scientificaccomplishments of the alumni (trainee) of the research center. 3. Fundingii) Results of current assessment made using said criteria and methods
1. The number of citations for the article that reported the discovery of orexins is 2668 and for thearticle describing narcolepsy episodes in orexin-deficient mice, the number of citations are 1660. 2.
Many researchers who received trainings as post-doctoral fellows in Yanagisawa Lab have become
professors and assistant professors of domestic and overseas universities, working in responsible
positions in research institutions and corporate settings. 3. The prospective Center Director, has
attained domestic funding worth 1.8 billion yen (US$22,500,000,) over five years as the Core
Researcher of the FIRST project. In addition, he secured an average of US$1,260,556 per year ofcompetitive funding in the U.S. in the last 5 years.
iii) Goals to be achieved through the project (at time of interim and final evaluations)(at time of interim)
1. The citation indices of our publications surpass those at other premier research centers for sleep
biomedicine, such as the Stanford Center for Sleep Sciences and Medicine. 2. It would be too early
to evaluate graduate students and post-doctoral fellows who are alumni of the research center.
(at time of final evaluations)
The citation indices of our publications surpass those at other premier research centers for sleep
biomedicine, such as the Stanford Center for Sleep Sciences and Medicine. 2. More senior alumniof the research center have attained independent positions in the academia and in the industry,both domestic and overseas
The total amount of competitive research funding raised by the prospective Principal
Investigators in the past five years is $44,316,704 averaging at $8,863,341/year. The University ofTsukuba will be responsible for the labor costs for the scientists who are full-time Principal
Investigators or researchers at the University before participating in this research center, and for the
full-time University staffs who were appointed to the administrative division of this research center.
The University will provide support for securing sufficient research space and for moving into newspace, and will be partially responsible for providing research funding. By providing the funding, theUniversity will support the installation of equipment and facilities, renovation of researchlaboratories, and the administrative management of the research center.
Program name: Funding Program for World-Leading Innovative R&D on Science and Technology(FIRST Program)
Project title: Molecular Mechanism and Control of Complex Behavior
Representative’s name: Masashi Yanagisawa
Funding period: 2010-2014

Exploiting the results ofpreviously-initiatedcenter-building efforts

Appropriations plan
(Exchange Rate: JPY/USD=80)

The reason why we believe that this WPI based on our existing FIRST program will succeed
Our forward genetic screening of mutagenized mice for sleep/wake abnormalities, which isenabled by the FIRST program, has been going on smoothly with promising positive results. Oursuite of cutting-edge equipment and experimental systems developed under the FIRST program
constitute an ideal environment where the prospective top Principal Investigators of this WPI Centercan productively explore their research ideas.
Our prospects after the FIRST program
Use the Health and Medical Science Innovation Laboratory as the core facility of the Center.
Total
FY

2012

2013

2014

2015

2016

2017

2018

2019

2020

2021

($ millions

3,127 5,770 7,020 7,020 7,020 7,020 7,020 7,020 7,020 7,020

65,057）WPI grant（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

2

Funding forpreviously-i
nitiated

1,008 1,730 1,730 1,730 1,730 1,730 1,730 1,730 1,730 1,730

16,5784,135 7,500 8,750 8,750 8,750 8,750 8,750 8,750 8,750 8,750

81,635center-building efforts(if any)
Total

Summary of hostinstitution’s commitment

How positioned within the host institution’s mid-to-long-term strategy plan
The Midterm Goals states: “strive for deep specialized expertise, open up new cross-disciplinary
fields, and achieve research results which are outstanding by international standards,” and“ambitiously open up new cross-disciplinary fields.” The WPI is in complete agreement with the
University’s Midterm Goals and Midterm Plan. We will specify “International Institute for Integrative
Sleep Medicine” for a Midterm Plan in the near future.
Concrete Measures
1) Provide at least the same level of resources as funded by this project.
2) Enable top-down decisions by the Center Director regarding personnel affairs and budgets.
3) Make necessary adjustments to assemble persons from other institutes of the University.
4) Amend the regulations, if necessary, to accommodate the new system of management.
5) Provide >5,000m2 of floor space that a “globally visible” premier research center deserves.
6) Support to sustain the Center after this program ends.

（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

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Research Center Project
Host institution
Chief entire-project
officer(Head of host institution)
Chief center-project
officer
Center director
Center name

University of Tsukuba
Nobuhiro Yamada, President
Masashi Yanagisawa, Center for Behavioral Molecular Genetics,
Professor and Director
Masashi Yanagisawa, Center for Behavioral Molecular Genetics,
Professor and Director
International Institute for Integrative Sleep Medicine
Sleep is a remarkably universal phenomenon in the higher animal
species, and its disturbances reduce mental and physical wellbeing.
However, the function of sleep and the mechanism for sleep regulation still
remain unknown; these questions are among the most important
challenges in modern neuroscience. The proposed research center will
gather the world prominent scientists from multiple research fields
contributing to the neurobiology of sleep. They will cooperate together toelucidate the fundamental principles of sleep/wake regulation, anddevelop new strategies to assess and treat sleep diseases as well as theclosely associated metabolic and mental disorders.
The general plan of the projectAt the proposed Center, we will aim at elucidating the fundamental
mechanism of sleep/wake regulation by combining the cutting-edge
methodologies of neurobiology, molecular genetics and physiology. We
will induce the fusion of medicine, chemistry, pharmacology and biology inorder to reveal the pathophysiology of sleep disorders and relateddiseases, and to develop methods for their treatment and prevention.
Through these research efforts, we will strive to reduce sleep disorders
and associated diseases, and to contribute to an improvement of physicaland mental health in today’s aging society with a dwindling birthrate.

Project summary

The Center’s overall structure
The proposed administrative structure will provide the Center Director
with sufficient authority to enable a timely and flexible decision-making.
The University of Tsukuba will host the Core site, while the Satellites will
be located at the University of Texas Southwestern Medical Center andthe Akita University. Although several research “groups” are depicted, theCenter will constantly encourage the exchange of information, materials
and personnel among and beyond these groups in order to facilitate thecreation of new ideas and the fusion of research fields.

（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

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The Center’s multidisciplinary network of Principal Investigators andresearch targets/objectives
Towards the Center’s unified research goals, world-class Principal
Investigators who are working in related but distinct research fields andemploying different methodologies, will closely cooperate with each otherwhile having their specific research targets and objectives.

Mission statement
and/or Center identity

The mission of this WPI Center is to be a multidisciplinary, international
hub for the research to elucidate the fundamental mechanism of
sleep/wakefulness, to develop strategies to regulate sleep, and tocontribute to enhancement of world health through the combat with sleep
disorders and associated diseases.

(1) Target research field
Name of the target research field
Sleep biomedicine
Sleep biomedicine, as defined here, is an inherently interdisciplinary field in terms of
methodology, spanning molecular genetics, cellular biology, neurophysiology, neurochemistry,
pharmaceutical sciences, medicinal chemistry, and clinical and social medicine. While focusing on
sleep, the field is also interdisciplinary with respect to its integral research targets, e.g., studying
mood disorders as well as metabolic diseases that are closely associated with pathological variations（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

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in sleep/wake states and sleep deficiencies.
Importance of the target research field
Sleep is a behavior that everyone experiences daily and it takes up as much as one third of one’s
entire lifetime. From ancient times, natural philosophers and scientists have been fascinated bysleep, especially by its association with loss of consciousness and dreaming. However, the very
fundamental mechanisms of sleep and its raison d’être remain still unknown today. While sleep has
been a black box stubbornly resisting scientists’ challenges, its medical and social importance is veryclear. Healthy sleep is necessary for maintaining our mind and body fitness; lack of sound sleep not
only causes a reduction in higher brain functions including memory and decision making, but also
increase the risk of mood disorders such as depression. In developed countries, the prevalence rateof sleep disorders that prevent people having healthy sleep is around 15%, with the lifetime
prevalence more than 30%. The underlying factors behind this problem include the increasingly
nocturnal lifestyle of today’s societies, presence of shift workers who account for about 20% of theworking population, and an increase of the elderly population. Deficiencies in healthy sleep causesignificant social losses, and are linked to car accidents due to excessive sleepiness, increased
prevalence of mood disorders, increased suicide deaths, and an increased caregiving burden due towandering and delirium in the elderly. Thus, while sleep has been a perpetual topic of scientificinquiry that keeps attracting many great minds, it is also a field where the society demands thedevelopment of strategies to remedy sleep disorders and associated diseases. On this account, theimportance of sleep as the target research field is clear.
As for the current trend of the field, triggered by the reports by Yanagisawa, Mignot, Siegel andtheir colleagues that a deficiency of the hypothalamic neuropeptide OREXIN is the root cause of thethen-mysterious sleep disorder NARCOLEPSY, a consensus has been formed by most researchers
in the field that orexin constitutes one of the centerpieces of the neural circuitry regulating sleep andwakefulness. Moreover, multiple pharmaceutical companies are currently focused on developing
new classes of sleeping pills (including those targeting the orexin pathway), indicating the consensus
among the domestic and overseas pharmaceutical industries that this field is highly important for
drug discovery.
Existing domestic and overseas research centers in similar fields
The University of Tsukuba Center for Behavioral Molecular Genetics, which is the foundation of
the present proposal, is the only multi-investigator research center in Japan that is specificallyfocusing on sleep biomedicine. This has been operated under the Funding Program forWorld-Leading Innovative R&D on Science and Technology (FIRST Program) of the Cabinet Officeof Japan, entitled “Molecular Mechanism and Control of Complex Behaviors,” with Masashi
Yanagisawa as the Core Investigator. As for sleep research centers in overseas countries, a numberof large research institutes around the world host such sites: More than 10 centers in the U.S.,
including the Stanford Center for Sleep Sciences and Medicine; two research centers in England;and some additional in other countries such as Australia.
Reasons why the project fit for this call for proposals
1) Japan’s expertise and international appeal
Japan has been producing a number of researchers who have made significant accomplishmentsin the field of sleep biomedicine. In particular, contributions to narcolepsy research have been
immense, including Yutaka Honda who was the first to elucidate an important association between
narcolepsy and immunity. Masashi Yanagisawa and Takeshi Sakurai discovered the neuropeptide
orexin and unraveled pathophysiological mechanisms of narcolepsy. This is arguably one of themost significant discoveries in the past 50 years of sleep research, which has created a new avenueof inquiry in the field: the two papers describing the discovery of orexin and the narcolepsy
phenotype in orexin knockout mice have been cited more than 4,400 times combined. While
primarily focusing on sleep, they have been conducting various behavioral studies that are related tosleep. Hiromasa Funato and Yanagisawa elucidated the potent role of orexin in basal metabolism
and body weight regulation, uncovering the possibility of drug discovery for metabolic diseases. In
part due to the wide recognition of these contributions, Yanagisawa has been selected as one of the
Principal Investigators for the FIRST Program (2009-2013) of the Cabinet Office of Japan, which has
allowed him to intensively promote sleep research at his new Center hosted by the University of（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

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Tsukuba.
Japanese researchers have also contributed prominently to the studies on sleep-inducing
substances. Especially noteworthy are the discovery of the sleep-inducing effect of prostaglandin D2
by Osamu Hayaishi and Yoshihiro Urade, and the revelation of its molecular mechanisms throughthe adenosine pathway. As seen here, the accumulation of sleep researchers’ continuous efforts andaccomplishments, as well as the research environment that made it possible, constitute Japan’s
strong expertise in the field of sleep biomedicine. Moreover, the present WPI-Focus, if funded, willallow Yanagisawa to fully base his research back in Japan as the full-time Center Director, movingfrom the University of Texas Southwestern Medical Center (UTSW) where he has been conducting
his research for over 20 years. His presence will further elevate the level of Japan’s expertise in
sleep biomedicine.
The international appeal of creating a center in Japan for the target research field owes in part tonumerous contributions made by Japanese researchers in this field and related research areas. The
proposed center has an international appeal to it not only because of the Japanese researchers
gathered at the Center but also the participation of the several prominent U.S. researchers best
represented by Joseph Takahashi, who has made Nobel-worthy contributions to uncover themolecular mechanisms underlying circadian rhythms including the discovery of one of the first clock
genes. The pool of these prominent researchers will make the Center further internationallyappealing, which will attract younger talents around the world. However, while being attracted to theexcellent research accomplishment and environment of Japan, it is true that there are many among
foreign researchers who feel uneasy about living and conducting research in Japan. Here, having
Yanagisawa as the leader will be a great help. Yanagisawa has been based at an American
university for over 20 years while sustaining his mental identity as Japanese; his experiences (bothas an U.S.-based researcher returning back to Japan, and as a person who has lived in America as a“foreign immigrant”) will allow him to manage the proposed center by creating a research
environment that is friendly to foreign researchers. Building on top of the strong tradition of Japan’s
sleep research, the Center will aim to become an international hub of sleep biomedicine by gathering
excellent young researchers from within and outside of Japan.
2) Future development and sustained, multidisciplinary research accomplishments
Despite the recent progress, it is fair to say that the field of sleep biomedicine is still in a very
naive and immature state compared to other fields of behavioral neuroscience. There have only
been relatively limited strings of definitive findings such as the importance of orexin. The circadianrhythm research saw an explosive progress after Takahashi’s discovery of the Clock gene. In thisanalogy, today’s sleep neurobiology looks as if it is the night before the impending discovery of its
own “Clock.” However, this also means that a similarly explosive progress in sleep biomedicine will
likely start in the near future. We will aim at seizing that moment. Moreover, sleep/wakefulness is
closely tied with energy metabolism, and the associations between sleep disorders and metabolic
syndrome are expected to become an increasingly major topic in sleep biomedicine in the near
future. This proposed center, pursuing the interface of sleep/rhythm and metabolism as one of its
main research objectives, is well prepared for the future.
At the University of Tsukuba Center for Behavioral Molecular Genetics led by Yanagisawa, that isthe basis of the present center proposal, we are fully operating a large-scale sleep recording system
for mice (capable of simultaneously EEG sleep-record from up to 100 mice), as well as a
cutting-edge, real-time optical visualization system for the neuronal activity in deep brain structures.
As for the generation and cross-breeding of genetically engineered mouse strains that can frequently
become the rate-determining step for the research, we have already produced and will continue to
produce numerous mouse lines for cell type-specific and time-dependent control of multiple genes ofinterest, including the orexin related genes. Thus, we have established a core of the cutting-edge
research environment; the present proposal will allow us to expand and improve this coreenvironment into a globally visible, long-term sustainable hub of multi-investigator cooperation.
In order to make the proposed center into a truly interdisciplinary site for the “fusion of research
fields,” the following researchers will participate: Hiroshi Nagase, who has an outstanding trackrecord in the field of medicinal chemistry, including his successes in developing first-in-class,marketed drugs in two different clinical areas; Junichi Hayashi, who is the first in the world tosucceed in producing a mouse strain termed the “mito-mouse”, a mouse harboring pathogenic
mutations in the mitochondrial genome; Akiyoshi Fukamizu, who has been making outstanding（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

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contributions to the understanding of the molecular mechanisms of metabolic syndrome andhypertension through intracellular signaling pathways and the regulation of gene transcription; andHitoshi Shimano, who has made significant accomplishments in lipid metabolism and lipid-induced
intracellular signaling pathways. The active participation of these researchers will facilitate theintegration of research themes interfacing sleep/wake regulation, cellular and organismal
metabolism, and the endocrine control, aiming at the creation of a new research modality.
We realize that the flow and provision of new ideas from the clinical setting back to the researchlaboratory is essential for the long-term sustained development of top-notch research, e.g.,suggesting a hypothesis based on findings gained from sleep disorder patients that can be tested ina mouse model. Participating in the proposed center for this purpose is Tetsuo Shimizu, one of thevery few psychiatry professors in Japan who is specialized in sleep disorders. Since many of theresearchers who are participating in the Center use genetically engineered mice as their routine
resource, Satoru Takahashi will also actively participate, who is the Director of the Laboratory Animal
Resource Center at the University of Tsukuba. His core-facility support will be essential, including thegeneration, transportation and management of transgenic mice.
Thus, the proposed center, while having its sharp focus on sleep biomedicine, will have a truly
multidisciplinary pool of researchers gathered from within and outside Japan. Having top researcherswith varying backgrounds and methodologies closely interacting together under a unified research
focus will allow the Center to sustain a world-class level of research in the target field for long term.
(2) Research objectives
The research objectives that the proposed center seeks to achieve are: 1) elucidation of thefundamental mechanisms of sleep/wake, 2) elucidation of molecular pathogenesis of sleep disorders
and related diseases, and 3) development of treatments for sleep disorders.
1) Elucidation of the fundamental mechanisms of sleep/wake[Research objectives to be accomplished by the end of the grant period]

Identification of new key genes involved in sleep/wake regulation.
Understanding the mechanistic principles of neural circuitry for sleep/wake regulation.

Our current knowledge on sleep/wake regulation is actually quite limited when judged under the
rigorous standards of today’s neuroscience. Among the limited tidbits is the notion that the lateralhypothalamic orexin neurons and the wake-active monoaminergic and cholinergic neurons of theclassical ascending activation system, together with the sleep-active GABAergic neurons of thepreoptic hypothalamus, likely constitute important parts of the executive circuitry for sleep/wakeswitching. Orexin neurons are clearly important for the stability of the switch. We know that thesleep-inducing substance adenosine (which is blocked by caffeine) is importantly involved in theregulation of the “depths” of non-REM sleep. We know that these executive systems are powerfully
governed by the circadian clock in the suprachiasmatic nucleus and by the presumed “sleep
homeostat” somewhere in the brain. Over all, our current level of understanding is rudimentary at
best. We will conduct precise neurophysiological analyses of these known components. We will
dissect neuronal and molecular mechanisms of sleep regulation by circadian clocks andsleep-inducing substances. At the same time, we will use a completely blind (unbiased) genetic
approach in order to identify new and unexpected genes that are importantly involved in theregulation of sleep/wake.
[Approaches necessary to accomplish research objectives]

Forward genetic approach to identify new key genes involved in sleep/wake regulation(Yanagisawa, Funato, Takahashi, J)
Considering the current state of the field where the fundamental principles of sleep/wakeregulation are still hidden inside a black box, an unbiased approach that strategically triggers
serendipity is essential in order to get closer to the very nature of sleep. Under the situation, we
believe that the best approach is the forward genetics in mice that Takahashi used beautifully
when discovering the Clock gene without having a biological hypothesis. The forward genetic
screen of randomly mutagenized mice for abnormal sleep/wake patterns was initially started as acollaboration of Yanagisawa and Takahashi, J at UTSW. The project has now been expanded as
one of the major pillars of the FIRST Project at the University of Tsukuba, where we also
（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

5

collaborate with Shigeharu Wakana at RIKEN BioResource Center in Tsukuba (Partner
Institution in this proposal). The large-scale screening at Tsukuba has been carried out smoothlywith a sustained throughput of 60-80 mice screened per week. We have so far screened ~4,000
mice by EEG/EMG-based true sleep analysis, and detected at least 4 pedigrees of mice
exhibiting marked, heritable abnormalities in sleep/wake. At present, the project is in the stage ofidentifying the causative gene by SNP-based linkage mapping and whole-exome sequencing,while continuing the primary screen. The heritable sleep abnormalities so far confirmed include:
substantially increased wakeful time, substantially increased non-REM sleep time, and markedly
abnormal REM sleep architecture. We believe that these strong phenotypes are caused bymutations in the genes that function within the core machinery of sleep/wake regulation. We will
directly close in on the regulatory mechanism of sleep/wake by discovering new
sleep/wake-regulating genes from these mutant mice.


Optogenetic and pharmacogenetic approach to understand the mechanistic principles ofneural circuitry for sleep/wake regulation (Yanagisawa, Sakurai, Liu)
Orexin is clearly required for normal sleep/wake control; orexin deficiency causes narcolepsy,
in which a highly destabilized sleep/wake states is the salient feature. However, we still do not
fully understand how exactly orexin functions to promote wakefulness and stabilize sleep/wakeswitching. We are pursuing various novel optogenetic and pharmacogenetic technologies inorder to real-time visualize as well as manipulate the activities of specific neuronal populations
involved in sleep/wake control. Yanagisawa and Sakurai, long-term collaborators, have been
establishing sophisticated experimentation systems using the latest, cutting-edge technologies
available in today’s neuroscience. Liu is an expert on the RNAi pathway, which he has been
dissecting through sophisticated biochemistry. At the proposed research center, he will jump in to
the field of sleep neurobiology and examine the regulation of sleep/wake by brain micro-RNAs, ofwhich the function in the CNS largely remains a mystery. By combining these various methods,
we will clarify the principles of neural circuit operation that controls sleep/wake behaviors.

Elucidation of the mechanisms of action of sleep substances (Urade and Greene)
Urade has investigated the mechanism for the sleep-inducing action of prostaglandin D2 anddiscovered that it was mediated by adenosine. Greene has generated and examinedbrain-specific adenosine receptor-deficient mice, and found out that the effect of sleep
deprivation on the depths of non-REM sleep is remarkably reduced under a deficient adenosine
signaling. However, because adenosine is ubiquitously present and can be generated andmetabolized by all cell types, it has been difficult to elucidate how its local extracellularconcentration is regulated in a manner that is relevant for sleep regulation. At this research
center, the mechanisms of action of sleep-inducing substances, especially that of adenosine, will
be further investigated and how it relates to the homeostatic mechanism of the sleep/wake will be
examined.

Elucidation of molecular mechanism of circadian rhythm and impacts of its disruption on
sleep (Takahashi and Green)
The identification of the Clock gene by Takahashi triggered an explosive advancement in theunderstanding of circadian clock mechanisms. Recently, it has become increasingly clear that
disruption of clock genes can trigger dysregulation of insulin secretion and other metabolic
abnormalities, suggesting a strong link between disruptions of circadian rhythm and aspects ofmetabolic syndrome. Takahashi will continue these lines of investigation, linking the sleep
abnormalities, circadian rhythm disruptions, and metabolic dysregulation. Green studies
molecular mechanisms that link the circadian rhythm to metabolic syndrome through theresearch on the circadian-regulated mRNA 3’-adenylase nocturnin. At the UTSW Satellite of thisresearch center, they will study how the circadian rhythm and sleep are related and themultifaceted impacts of disrupted circadian rhythm on individuals. Takahashi will also continue toprovide his expertise in gene identification in mutagenized mice (see above).

2) Elucidation of molecular pathogenesis of sleep disorders and related diseases[Research objectives to be accomplished by the end of the grant period] Identification of peripheral organ-brain interactions in the regulation of sleep/wakebehavior.
 Identification of a molecular link between intracellular events and sleep-related behaviors
in vivo.
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6

Irregular sleep/wake cycle and insomnia are a risk factor for metabolic syndrome as well as formood disorders. However, the mechanism for the link is unknown. Using genetically engineeredmouse models, the possible molecular links between sleep/wake, mood regulation, and metabolic
control will be studied.
[Approaches necessary to accomplish research objectives] Physiological and endocrinological research on the association of abnormal metabolism
and sleep/wake disruption (Shimano, Funato, Takahashi)
Shimano has been making significant contributions for the elucidation of intracellular signaling
and transcriptional control related to lipid/cholesterol metabolism. Recently, he has generated
mice that have an abnormal lipid composition in the brain by disrupting the gene for a lipid
modification enzyme. The effects of the lipid composition on the brain function are mostly still
unknown. Studies will be conducted to determine the behavioral consequences of the abnormal
brain lipid composition and metabolism, including sleep/wake abnormalities. Funato has
elucidated the complex regulation of feeding behavior and body weight by orexin neurons. He willcontinue to dissect the neural circuits for orexin that are involved in sleep/wake, energy
homeostasis, and glucose metabolism. By combining retrograde trans-synaptic viral vectors andtransgenic carrier mice, the cross talk between the brain and the peripheral organs in the energy
metabolism will be investigated.


Investigation on the link between sleep/wake disruptions, metabolic dysregulation, andcellular metabolism/respiration and signaling (Hayashi and Fukamizu)
Hayashi is a globally recognized expert in the cell biology and genetics of mitochondria, theintracellular generators of energy. At the proposed center, his laboratory will focus on thebilateral relationship between the mitochondrial and cellular energy metabolism and sleep/wakeat the organismal level. Hayashi has succeeded in producing mice carrying the pathogenic
mutant mtDNA, and by using these mice, effects of mitochondrial dysfunction on sleep/wakebehavior will be examined. Reciprocally, the mitochondrial functions will be studied insleep-deprived mice and in transgenic mice showing sleep/wake abnormalities. Fukamizu will
study how the sleep/wake cycle and energy/glucose metabolism are related by using varioustransgenic mice with altered FOXO transcription factors and other intracellular signaling
pathways. We will aim at linking the metabolic/respiration pathways at the cellular level to thechanges occurring at the organismal level such as sleep/wake and systemic energy
homeostasis.

3) Development of new treatment methods for sleep disorders[Research objectives to be accomplished by the end of the grant period]
 Develop drug-candidate compounds for sleep-related disorders which advance to clinicaltrial Develop “good sleep” program, a multidimensional non-drug intervention, to prevent
sleep-related disorders based on the evidence of basic and clinical studies.
We will develop new drug-candidate compounds modulating sleep/wake that are different fromexisting sleep-inducing agents or psychostimulants in their mechanism of action. We will also
develop methods for prevention and early intervention to sleep disorder and related diseases. This
includes behavioral modifications to specific aspects of lifestyle, such as sleep, diet, exercise, andstress-coping. It is likely that these new drugs and intervention programs are not only effective forsleep disorders but also for mood disorders and metabolic diseases. We will utilize such associations
in order to elucidate the molecular mechanisms behind the association.

[Approaches necessary to accomplish research objectives]
 Development of drug-candidate compounds targeting orexin receptors (Nagase,Yanagisawa, Funato)
Triggered by the discovery of the prominent role of orexin in maintenance of wakefulness by us
and others, several pharmaceutical companies have developed orexin receptor antagonists. The
most advanced of those antagonists, suvorexant from Merck, has gone through a large Phase III
clinical trial as a sleep-inducing drug, producing highly promising results. We are taking a noveland opposite approach: instead of inducing sleep at bedtime, our drug shall elevate the level of（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

7

wakefulness during daytime and that will naturally bring about sound sleep at night. Orexin
receptor agonists should be also useful as the mechanistic replacement therapy fororexin-deficient individuals, accounting for >90% of narcolepsy patients. Agonists may also
prevent and reduce metabolic syndrome, since Funato has demonstrated that orexin is a
net-negative regulator of energy homeostasis. Towards these goals, we have carried out ahigh-throughput screening of a library of ~250,000 drug-like compounds at UTSW and identified
several distinct chemical classes of orexin receptor agonists. Based on information obtained bythis screening, we will embark upon a serious medicinal chemistry efforts in order to further
improve compounds’ potency, blood-brain-barrier permeability, and oral bioavailability. We fully
realize that making a CNS-available agonist for peptidergic receptor is a formidable challenge inmedicinal chemistry. Nagase’s experience of creating two first-in-class marketed drugs will befully utilized here. Candidate agonists will be subjected to various cell-based, ex vivo and in vivo
assays, not only in order to test them as drug candidates but also to use them as
pharmacological tools for further dissecting the orexin biology.


Identification of novel sleep/wake modulating substances and their mechanism of action
by in vivo screen of compound libraries (Funato, Yanagisawa, Nagase)In addition to the above-described target-based approach of drug discovery, we will attempt a“black-box” in vivo screen of small-scale compound libraries in order to identify novel sleep/wakemodulators. As mentioned above, because of the ongoing forward genetic screening forsleep/wake mutant mice, we already have a large-scale system for mouse sleep recording fully
up and running. We will utilize this facility to screen a pre-selected subset of 1,000-2,000
drug-like compounds in vivo, by administering a mixture of ~10 compounds per mouse(multiplexing) while EEG sleep-recording them. If a novel (or unexpected) sleep/wakemodulating compound is found, we will decipher its molecular target and mechanism of action,and initiate medicinal chemistry efforts to improve the initial hit. This will hopefully lead not only tothe discovery of a new sleep-regulatory pathway but also to a novel drug candidate.



Development of new assessment and preventive measures for sleep disorder patientsand high risk groups (Shimizu and Matsuzaki)
Workers in modern societies are constantly deprived of sleep and immersed in environments
where they can develop full-blown sleep disorders and mood disorders. It is important to identify
a high-risk group for developing sleep disorders at an early stage, and perform the appropriate
intervention. At the proposed research center, we will try to remedy sleep disorders not only byusing drug treatments but also by providing lifestyle guidelines for getting a healthy sleep,
nutrition, and exercise. We will also develop appropriate assessments and measures in order toprevent high-risk groups from developing serious diseases. Shimizu has been single-handedly
undertaking a majority of orexin peptide measurements in Japanese patients, and established a
network between patients and medical institutions concerning sleep disorders and related
conditions. Matsuzaki, as a leader of the industrial psychiatry field, has an established network in
the client industries. Such networks allow us to verify the accuracies of assessments andefficacies of intervention. Matsuzaki and Shimizu function as an interface between the clinicalenvironment and research laboratories, e.g., by translating knowledge gained from mousemodels to patients, and conversely, by providing laboratory-testable hypotheses derived from thefindings in patients. Networks Shimizu and Matsuzaki have generated will increase the visibilityof this research center, and will also be tremendously helpful in the future clinical trials of thesleep disorder drug being developed by Nagase and Yanagisawa. In addition, Matsuzaki also
specializes in the field of aerospace psychiatry and is a member of the Japan Aerospace
Exploration Agency (JAXA), which conducts studies on sleep and psychological stress under
microgravity by using astronauts as unique research subjects.

(3) Managementi) Center director

Masashi Yanagisawa (52 years old), Center for Behavioral Molecular Genetics, Professor andDirector.
Specialties: Neuroscience, Pharmacology.
Professor Yanagisawa is one of few scientists who made two outstanding discoveries of bioactive
peptides. Both discoveries revolutionized the research field and have brought clinical benefits.

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8

In 1988, when he was a graduate student, he and his colleagues identified “endothelin” as apotent vasoconstrictor factor produced by endothelial cells. Subsequently, he and his colleagues at
the University of Tsukuba succeeded in cloning endothelin receptors. He was highly recognized forthe discovery of endothelins and their receptors so that when he was 31 years old, he was recruited
by Joe Goldstein and Mike Brown to the University of Texas Southwestern Medical Center, andstarted his own lab as an associate professor and associate investigator of the Howard Hughes
Medical Institute. As a PI, he succeeded in cloning of endothelin converting enzymes. During thecourse of his research on gene targeted mice, he and his colleagues have unexpectedly
demonstrated that the endothelin pathways are important in the embryonic development of neuralcrest-derived tissues, and have led to the discovery that endothelin and endothelin receptor
mutations cause Hirschsprung’s disease and related neurocristopathies in humans. In adultpathophysiology, endothelin is implicated in various conditions involving abnormal vascular tone andremodeling, and endothelin receptor antagonists are in clinical use as a mainline drug for thetreatment of pulmonary hypertension since 2001.
Around 1995-1996, he started a risky endeavor of finding novel bioactive molecules by“de-orphanizing” orphan G protein-coupled receptors. In 1998, his group published the discovery of“orexins,” endogenous neuropeptide ligands for two orphan G protein-coupled receptors. Orexin isexpressed exclusively in the lateral hypothalamic area, which was considered a “feeding center.” In
the following year, his laboratory unexpectedly discovered that orexin-deficient mice suffered fromnarcolepsy, a sleep disorder characterized by excessive daytime sleepiness and abnormal intrusionof REM-sleep phenomena. Subsequent results from his laboratory indicate that supplying
exogenous orexin peptides, either transgenically or pharmacologically, completely rescues
narcoleptic mice that lack endogenous orexin neurons. Since it has been shown that the vast
majority of human narcoleptic patients are orexin-deficient, Yanagisawa’s studies open up the
possibility of replacement therapy of the disease using orexin receptor agonists. The orexins haveturned out to be a major key to understanding wakefulness, motor control during sleep, andmotivation and addiction during wakefulness. Recently, he and his colleagues showed the criticalrole of orexin receptor type 2 in regulating body weight, which drives the current drug discovery
project for anti-obesity drug. For his outstanding achievements, he was elected to a member of the
U.S. National Academy of Sciences in 2003.
Because he has run his own lab in the U.S. for more than 20 years, he is familiar with thestrengths and limitations of both the research and administrative systems of top U.S. research
universities. He also conducted his own lab in Japan by the research funding program, Exploratory
Research for Advanced Technology (ERATO), and now running his own lab at the University ofTsukuba by Funding for World-Leading Innovative R&D on Science and Technology (FIRST). Thus,
he is the right person to bring merits and strengths of the U.S. academic system to Japan. He has apersonal network of prominent researchers around the world, which makes him the most appropriate
person as the Center Director to build a research center functioning as the “hub for research
excellence.”
Currently, Professor Yanagisawa spends approximately half the year working in Japan to run his
lab at the University of Tsukuba. If the present WPI application is funded, he intends to retire from theHoward Hughes Medical Institute and will be fully committed to the full-time position as the Center
Director.
ii) Administrative director

Katsutoshi Goto (69 years old), Professor Emeritus, University of Tsukuba
Professor Goto served as a professor of the Department of Pharmacology, Institute of Basic
Medical Sciences, University of Tsukuba from 1990 to 2006, engaging himself in intensive researchand education. He has profound understanding of the research objectives and methodologies of theprospective research center. He has plentiful exchange experiences with overseas researchers andis excellent at communicating in English.
When he was an associate professor at the Department of Pharmacology, he was involved in the
research study that led to the discovery of endothelin, which allowed him to build a long and trusting
relationship with the prospective Center Director, Masashi Yanagisawa.
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9

He served as the Director of the Institute of Basic Medical Sciences, University of Tsukuba andalso as the Director of Center for Tsukuba Advanced Research Alliance (TARA Center). He hasabundant experiences with administrative affairs related to the conduct of research. He has a broad
range of human connections in the University of Tsukuba because of his history. As described, he is
the most appropriate personnel as the prospective Administrative Director of the research centerfrom the viewpoints of his understanding for research, proficiency in language, relationship with theprospective Center Director, and relationship with the host institute.
iii) Administrative staff composition
We will establish a strong supportive organization in order to decrease the burden of
administrative obligations of scientists so that they concentrate on their research. In order to enableprompt decision-making and resolute implementation, increase the independence and autonomy ofthe proposed research center and establish a top-down administrative system headed by the Center
Director. Moreover, by fully utilizing the long-term experience of the Center Director at an American
university, we will put persistent efforts to reassess the research and administrative organizations. In
addition, by assigning several full-time members of the University administrative staff to the research
center, we will make best use of the University’s know-how and also enable an organic coordination
with the administrative organization of the University.
1. Composition of the administrative staff
Under the supervision of the administrative director who is thoroughly knowledgeable in both theresearch contents of the center and the administrative affairs of the national university corporation,
the administrative staff will be composed of the administrative director, assistant administrative
director, and the following three sections.
・General affairs section (5 staff members)
General affairs section will be engaged in legal affairs, general affairs, personnel affairs,
employment, travel, work management, public relations (outreach activities), symposia, conferences,and international affairs. One full-time University staff member who has a thorough knowledge ofgeneral affairs will be assigned to the Center. With regard to the support for a large number of foreign
researchers coming to the Center, we will take full advantage of the City of Tsukuba as aninternational scientific research park, and commission it to the Japan International Science andTechnology Exchange Center (JISTEC) as required.
・Accounting section (4 staff members)
Accounting section will be responsible for budget management and execution, procurement, anddomestic and overseas transfer of funds and supplies. One full-time University staff member who
has a thorough knowledge of budgetary and accounting will be assigned to the Center.
・Research fund section (3 staff members)
The research fund section will be in charge of a wide variety of tasks related to competitive
research funds, including information collection, application support, administrative affairs, andsupport for report preparations. One full-time University staff who is highly experienced in the affairs
for securing research funds and knowledgeable of the governmental systems will be assigned to theCenter.
2. Use of English as the official language
English will be used as an official language at the research center. All assigned staff members
will be fluent in spoken and written English, except for the people who have specific skills that cannot
be replaced by any other people. Documentation will be in English or bilingual as much as possible,
except where it has to be in Japanese for external reasons.
3. Recruitment and development of quality staff members
We will preferentially hire people with overseas experiences and/or with an excellent command in（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

10English language. The TOEIC/TOEFL scores and particularly the writing and speaking abilities will
be considered as important factors for hiring. English language training sessions will be conducted
regularly for the staff members. Once every two years, overseas training sessions will berecommended even to administrative staff members, providing them the opportunities to see the“cultural melting pot” and directly learn from the open-minded attitudes welcoming foreigners. Theirexperiences from such sessions will be used for creating a positive environment for foreign
researchers at the Center.
iv) Decision-making system
In order to facilitate efficient and flexible administration of the research center, the Center Director
will have the sole authority of decision-making related to the personnel and management matterswithin the Center. The Center Director has the entire authority relating to the general management of
the Center except for the removal of himself and the determination of his own salary. He has theauthority over recruitment, hiring, contract renewal, salary, research space allocation, evaluation,and promotion regarding all Principal Investigators, visiting researchers, and post-doctoral fellows
who are invited to the Center. He also has the right to make decisions on behalf of the Center,
related to contracts with its Satellite institutes and the assignment and dismissal of researchers as
the Center’s Satellite Principal Investigators. In addition, he has the authority over the hiring andcontract renewal of the Center’s administrative staff members, excluding the full-time University staff
members assigned to the Center by the University.
An external advisory board will be established to provide the Center Director with advice on theCenter management by using video conference. In order to facilitate center-wide discussions ofadministrative matters and personnel recruitment, the Center Director can create and convene, as
needed, various internal committees comprised of the Administrative Director and Principal
Investigators.
The Administrative Director will supervise the administrative division and provide an environment
where researchers can focus on their research. The Principal Investigators can makerecommendations to the Center Director regarding the hiring of post-doctoral fellows and technicalsupport staff members in the research laboratory he/she is supervising. Regardless of the position,anyone who is participating in this Center can offer his/her opinions regarding the management or
treatment directly to the Center Director.
v) Allocation of authority between the center director and host institution
By positioning the prospective research center as an independent research institute of the
University, it is intended to assure a wide range of independent management, including personnel,
facility management, and budget execution. As a result, under the strong leadership of the Center
Director, a dynamic and prompt organizational management will be enabled. Specifically, whereas
the President of the University has the authority to elect or dismiss the Center Director, the Center
Director has a wide range of authorities regarding the general management and internal
administration of the research center. The Center Director has authorities over hiring, contract
renewal, salary, allocation of research space, evaluation, and the promotion of the invitedresearchers, including Principal Investigators and post-doctoral fellows. He has the authority to hire
and renew the administrative staff members, excluding the full-time staff members of the University
assigned to the Center. This type of system is widely seen and most usual in the major universities
and research institutes in the U.S., which will make the most of the Center Director’s research andadministrative experiences in the U.S. Moreover, the Center will establish and maintain an intimate
cooperation channel with the office of the President of the University and the Vice President incharge of research. When an important and legitimate issue arises regarding the management of theCenter that requires amending or revising the current regulations and codes of the University, thePresident will earnestly consider doing so through his top-down authority, while incessantly
examining the system so that a prompt and flexible response is possible.
(4) Researchers and other center staffs, satellites, partner institutionsi) The “core” to be established within the host institutiona) Principal Investigators (full professors, associate professors or other researchers of comparable
standing)（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

11

Numbers
At beginning
Final goal

Those inexisting

At end of FY 2012

(Date: month, year)(October, 2013)

center-buildin
g project

Researchers from within
the host institution
Foreign researchers invitedfrom abroad
Researchers invited from otherJapanese institutions

7

0

7

7

0

0

2

4

0

0

2

4

Total principal investigators

7

0

11

15

（At beginning）
The proposed research center will be inaugurated with the 7 existing faculty members of the
University of Tsukuba (Masashi Yanagisawa, Hiromasa Funato, Ichiyo Matsuzaki, Jin Shimano,
Junichi Hayashi, Akiyoshi Fukamizu, and Satoru Takahashi) as Principal Investigators.
（At end of FY2012）
The Center will have invited Takeshi Sakurai (currently at University of Kanazawa) to the
Tsukuba Core as a Principal Investigator. The proposed Satellites will have been installed at the
University of Texas Southwestern Medical Center and at the Akita University. Joseph Takahashi,
Carla Green (Texas), and Tetsuo Shimizu (Akita), will join as Principal Investigators at the Satellites.
（Final goal （circa October, 2013）
All of the 15 proposed Principal Investigators will have joined the Center by FY 2013. Yoshihiro
Urade (currently at Osaka Bioscience Institute), Hiroshi Nagase (Kitasato University), Robert Greene(UTSW), and Qunghua Liu (UTSW) will have been moved to the Tsukuba Core as Principal
Investigators. Especially, the Center will provide generous startup funds to the two Principal
Investigators recruited from abroad.
b) Total members
Numbers
At beginningThose in existing
center-building

At end of FY
2012

project

Final goal
(Date: month, year)(March, 2015)

Researchers

Principal investigators

Other researchers

Research support staffs
Administrative staffs
Total number of people
who form the “core” of theresearch center

41< 1, 2%>[ 8, 20%]7< 1, 14%>[ 0, 0%]34< 0 ,0 %>[ 8, 24 %]
17
14
72

7
< 0, 0%>[ 5, 71 %]0< 0 , 0%>
[ 0, 0%]]7< 0, 0%>[ 5, 71%]]
7
4
18

59
< 18 , 31%>
[ 9, 15%]11< 3, 27%>[ 1, 9%]48< 15, 31%>
[ 8, 17%]
19
14
92

115
< 35, 30%>
[ 35, 30%]
15
< 5 , 33%>
[ 1, 7 %]100< 30, 30%>
[ 34, 34 %]
40
14
169

（At beginning）
The Center will be started with the 7 Principal Investigators from the University of Tsukuba and（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

12

the members in their respective laboratories. Eighteen members will join from the FIRST program.
（At end of FY2012）
The members of the Sakurai laboratory will have joined the Tsukuba Core.
（Final goal（March, 2015）
All of the 15 proposed Principal Investigators will have joined the Center by FY 2013. The
members of the Urade and Nagase laboratories will have joined the Tsukuba Core. Two researchers
will have been recruited to the laboratories of Takahashi and Greene at the Texas Satellite. We will
employ all post-doctoral fellows through international solicitations; highly talented young scientists
will be recruited over the years. The Center will have approximately 150 researchers overall by theend of FY2015.
ii) Collaboration with other institutions[Satellite institutions]
1) University of Texas Southwestern Medical Center
A Satellite site will be installed at the University of Texas Southwestern Medical Center where
the prospective Center Director Masashi Yanagisawa has been conducting his research for over
20 years. As Satellite Principal Investigators, two world-leading researchers in the field of
circadian rhythm, Joseph Takahashi and Carla Green, will participate. A total of two WPI-funded
post-doctoral fellows will be hired for these laboratories. A close collaboration with the Takahashi
laboratory has been ongoing for over two years already, concerning the mouse forward genetics
project. His continued contributions will be essential in order to carry through the project. The
presence of Takahashi and Green will further elevate the global visibility of this WPI Center.
2) Akita University
We will establish a Satellite at the Akita University, which is by far Japan’s largest site forpatient-based clinical studies on the orexin system. The Satellite Principal Investigator, Tetsuo
Shimizu, is a professor of the Department of Neuropsychiatry, and has an extensive network ofpatients and medical institutions for clinical research of sleep disorders including narcolepsy.
In order to facilitate the progress of research based on intimate interactions between the Tsukuba
Core and the Satellite sites, we will have internet-based weekly video conferences. Also, these
Satellite Principal Investigators and the Center Director will regularly visit each other in person.
[Partner institutions]
1) RIKEN BioResource Center, Tsukuba
Shigeharu Wakana of the Technology and Development Team for Mouse Phenotype
Analysis, RIKEN BioResource Center, has identified a large number of pathogenic mutations
from their systematic ENU-mutagenesis screening in mice. He is also a Japan representative of
the International Mouse Phenotyping Consortium (IMPC). We have an ongoing close
collaboration with his team in our forward genetic screening and mapping of sleep/wake mutant
mice, which is a major pillar of the FIRST project. RIKEN BioResource Center will serve as apartner institution in the present proposal, and function as the local provider of
ENU-mutagenized mice, and as the core facility for systematic mouse phenotyping.

(５) Research Environmenti.

Provide an environment in which researchers can devote themselves exclusively to theirresearch, by exempting them from duties other than research and related educational
activities, and providing them with adequate staff support to handle paperwork and otheradministrative functions.

1. Support by administrative division
We will implement an administrative support system that will reduce the burden of administrative
obligations of researchers and allow them to devote themselves exclusively to their research. Our（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

13

administrative team will promptly respond to the intentions of the Center Director. Under thesupervision of the Administrative Director who has a thorough knowledge in both the science
research and the management affairs of national universities, the administrative division will function
autonomously and independently from the University administration. Specifically, the administrative
division will fully and promptly perform any necessary support for the conduct of research, including
legal affairs, general affairs, personnel affairs, employment, travel, work management, public
relations (outreach activities), symposia, conferences, international affairs, acceptance of overseas
personnel, budget management and execution, procurement, domestic and overseas transfer offunds and supplies, as well as the tasks related to competitive research funds, including informationcollection, application support, administrative affairs, and support for report preparations.
2. Exempting on-campus researchers from non-research institutional duties, while providing support
for their affiliated departments
Regarding those top researchers who are recruited to and participate in the Center from within
the University of Tsukuba, the Center will ensure that they can further their research without
hindrance, by cooperating with their affiliated departments. Those researchers will be exempted fromsome of their non-research duties at their affiliated departments. In return, we will compensate theiraffiliated departments by providing relevant personnel costs.
3. Living support
The University of Tsukuba promotes “Globalization as a matter of daily living” as one of theinstitutions that have been selected as a core university of the “Global 30” sponsored by the Ministryof Education, Culture, Sports, Science and Technology (MEXT). The town of Tsukuba has anadvantage of being built an international research park. The Japan International Science andTechnology Exchange Center (JISTEC) is located in Tsukuba and provides a wide range of living
support for researchers from foreign countries. Partly in collaboration with JISTEC, the Center will
provide various supports, including visa application, paperwork such as alien registration, openingbank account, purchasing insurance, and arranging for residence. The University of Tsukuba willoffer the university guesthouses and its affiliated housings nearby for the researchers (especiallyforeigners) and administrative staff members who are recruited to work in this research center. For
the researchers who visit the Center to attend seminars or to conduct collaborative research, various
accommodation facilities of the University will be available.
ii.

Provide startup research funding as necessary to ensure that top-caliber researchers invited
to the center do not upon arrival lose momentum in vigorously pursuing their work out ofconcern over the need to apply immediately for competitive grants.

For the independent researchers who are recruited to the Tsukuba Core from other institutions(especially those from overseas institutions), the Center will provide a sufficient amount of startup
research funding. The amount of the startup fund will be individually considered and negotiated, butwill be similar to startup funds in the U.S. academia under equivalent situations. It will be decided by
the Center Director who has plentiful experience in the U.S. academia. When it is time for them toapply for external funding, the administrative division will provide strong administrative support
through the entire application process.
iii.

As a rule, fill postdoctoral positions through open international solicitations.

In order for the Center to survive and stand out as an outstanding research center after 10 years,
it is imperative to recruit excellent young talents. International recruitment will be conducted by using
the following means to hire outstanding post-doctoral fellows.
1. Prominent international journals such as Nature and Science; 2. Personnel database JREC-IN(Japan Research Career Information Network) operated by the Japan Science and Technology
Agency; 3. Web sites of academic research societies such as the Japan Neuroscience Society; 4.
University of Tsukuba web site (in four languages); 5. Departmental web sites; 6. University ofTsukuba’s overseas offices; 7. Our overseas Satellite (public release by the University of Texas
Southwestern Medical Center), 8. Personal international networks of the Center Director andPrincipal Investigators.
The University of Tsukuba is equipped with various career and living support systems for thedevelopment of young researchers at all levels. By utilizing such systems, we will be aggressively
promoting the participation of outstanding post-doctoral fellows, especially foreign researchers and（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

14

female scientists.
The Center Director will strive to create an environment that attracts quality personnel by
aggressively outreaching to society, thereby increasing the visibility of the research center.
The young researchers working at the Center will strive to achieve research accomplishments
sufficiently high so that they will then be recruited by other institutions for the next career stage. This
will promote healthy personnel mobility, ultimately helping the Center to sustain its world premier
status.
iv.

Establish English as the primary language for work-related communication, and appoint
administrative personnel who can facilitate the use of English in the work process.

Needless to say, all science will be conducted in English at the Center. In addition, alladministrative staff members will be fluent in spoken and written English, except for the people whohave specific skills that cannot be replaced by any other people. Documentation will be in English or
bilingual as much as possible, except where it has to be in Japanese for external reasons.
The TOEIC/TOEFL scores and particularly the writing and speaking abilities will be considered asimportant factors when appointing administrative personnel. English language training sessions will
be conducted regularly for the staff members. Once every two years, overseas training sessions will
be recommended even to administrative staff members.

v.

Adopt a rigorous system for evaluating research and a system of merit-based compensation.
(For example, institute a merit-based annual salary system)
The President of the University will decide on the renewal and the salary of the Center Director.

The Principal Investigators and other independent researchers will be annually evaluated by theexternal advisory board, considering publications and their citations, invitations to international
meetings, level of external funding, generation of significant intellectual properties, etc. The Center
Director decides on the salaries of the Principal Investigators and other independent researchersconsidering the results of the annual evaluations.
The salaries of the other researchers and administrative staff members are decided by the Center
Director based on the opinions of the supervising investigator and Administrative Director,
respectively.
When inviting Principal Investigators and other independent investigators from outside of the hostinstitution, their salaries will be determined according to their research accomplishments andprevious salaries.
vi.

Provide equipment and facilities, including laboratory space, appropriate to a top world-levelresearch center.

The Center will be provided with a sufficient amount of floor space that can be favorablycompared, on a per-capita basis, with the floor spaces of premier research centers in the U.S. These
will include wet-lab spaces, dry-lab/office spaces, and animal housing spaces especially for mice.
Generous space for animal housing is absolutely essential considering the Center’s target research
field.
Specifically, the Center will be provided with all floors on the E Building of the University ofTsukuba Hospital, which will be vacated by January, 2013 into the new ward building currently underconstruction. The Center will continue to use the floors on the Health and Medical Science Innovation
Laboratory that are currently occupied by the FIRST Program. Together, the Center will be provided
with more than 5,000 m2 of research floor space. The Hospital E Building is located in close physicalproximities to both the Innovation Laboratory and the Laboratory Animal Resource Center, whichshould be highly advantageous. During the required renovation of the E Building, the Center will be
provided with temporary floors on the Laboratory of Advanced Research D.

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15

The building that houses the current FIRST Program, the Health and Medical Science Innovation
Building, was newly constructed in 2011, incorporating the recent design trend of overseas researchlaboratories. It has a coffee-break area on each floor, which can be a place for casualcommunications between researchers. On the top floor is a large, 200-people conference room. The
Center’s own seminar series will be held there, providing opportunities for exchanges among theCenter members and with other researchers on campus.
Regular intra-laboratory and Inter-laboratory research meetings will be held by using
internet-based video conferencing services (such as Skype), so that the meeting is attended by the
Principal Investigators and researchers at the Satellite sites. The prospective Center Director has
been managing his two laboratories across the pacific (Tsukuba, Japan and Dallas, Texas) for over
two years now. These spaces for communication will continue to function as the key facility of the
WPI center after its establishment.
The existing research facility for the FIRST program is equipped with shared capital devices suchas a system for large-scale mouse EEG/EMG recording and analysis, a fiber-optic fluorescence
confocal endo-microscope, a two-photon microscope with electrophysiology rigs, multiple sets ofslice and cellular patch-clamp station, and an ultra-low-power, wide-field confocal microscope.
Cutting-edge shared devices will be systematically acquired in the proposed center, according to therequirements of its laboratories.
Additional capital equipment will be available to the Center through the Open Facility function of
the University, which is scheduled to start sometime this fiscal year. This includes such equipment as
cutting-edge mass spectroscopy, super-high resolution ultrasound echo sonography for mice, and invivo luminescence/fluorescence imaging system for mice. This function will be expanded in stages,
and will make possible the use of the pioneering research facilities in the Tsukuba area.

vii.

Hold international research conferences or symposiums regularly (at least once a year) tobring the world’s leading researchers together at the center.

The prospective Center Director served as the organizer of the international symposium“Frontiers in Behavioral Brian Science ~ Solving the Mystery of Sleep” through the 2011 Funding
Program for World-Leading Innovative R&D on Science and Technology (open seminars of the
FIRST program). We could gather a total of 16 prominent researchers in the field as invited
speakers, including a Nobel Laureate (9 from the U.S., 3 from Europe, and 4 from Japan). The
symposium was conducted in English including all oral and poster presentations.
In order to create a “globally visible research center”, we will regularly hold similar symposia oncea year, and invited seminar series twice a month. Moreover, we will hold a retreat once a year for thedevelopment of students and young researchers, promotion of collaborative researches, and also an
increased sense of a family-like unity of the Center. Providing workshops at overseas Satellites will
also increase the visibility of the research center overseas.

viii.

Other measures, if any, to ensure that top-caliber researchers from around the world can
comfortably devote themselves to their research in a competitive international environment.

The University Research Administrator (URA) office of the University of Tsukuba (director: vicepresident in charge of research), which has been established as a part of the “Global 30” initiative by
the MEXT, will provide the Center with additional know-how on development strategies, international
cooperation, and compliance.
Graduate students conducting thesis studies at the Center will be, as a rule, all hired as research
assistants (RA). Based on the objectives of the 3rd and 4th Science and Technology Basic Plans, thelevel of their salaries will be the amount equivalent to living expenses. By providing reasonable
compensations, the graduate students will concentrate on their research activities as theirprofessional work. The prospective Center Director discovered endothelin when he was a graduate
student. In that spirit, the Center will promote creative researches through casual but intensive
discussions with young graduate students who have flexible and free ideas.

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(6) Indicators for evaluating a center’s global standingi) Criteria and methods to be used for evaluating the center’s global standing in the subject field
1.

Number of citations of published papers in the medium to long term
The degree of scientific contribution of research work is sensitively reflected upon thenumber of citations in the medium to long term.

2.

Positions and scientific accomplishments of the alumni (trainee) of the research center
When evaluating a research center in the U.S., positions that previous graduate students
and post-doctoral fellows acquire in the following years become an important evaluationindex.

3.

Funding
Since it is a reflection of the quality of the research plan and previous performances andcontributions, funding is an important evaluation index.

ii) Results of current assessment made using said criteria and methods
1.

As for the prospective Center Director’s work, the number of citations for the article thatreported the discovery of orexins is 2668 and for the article describing narcolepsy episodes
in orexin-deficient mice, the number of citations are 1660. These high numbers of citations
suggest that these articles are remarkable reports that greatly affected research activities ofother researchers in the field.

2.

The existing FIRST research core is so new and this way of evaluation is impossible at thispoint. However, speaking of the research laboratory of the prospective Center Director,
Masashi Yanagisawa, many researchers who received trainings as post-doctoral fellows
have become professors and assistant professors of domestic and overseas universities,
working in responsible positions in research institutions and corporate settings. The value ofsuch personnel network is very immense. Such real examples will attract excellent graduate
students and post-doctoral fellows to this research center.

3.

Masashi Yanagisawa, the prospective Center Director, has attained domestic funding worth
1.8 billion yen (US$22,500,000,) over five years as the Core Researcher of the FIRST
project. In addition, he secured an average of US$1,260,556 per year of competitive funding
in the U.S. in the last 5 years.

iii) Goals to be achieved through the project (at time of interim and final evaluations)(at time of interim)
1. The citation indices of our publications surpass those at other premier research centers forsleep biomedicine, such as the Stanford Center for Sleep Sciences and Medicine.
2.

It would be too early to evaluate graduate students and post-doctoral fellows who are alumniof the research center. However, some of them would have started to move their way up to
the next stage of various career paths, including those at overseas research facilities.

3.

Maintain the current level of research grant acquisition.

(at time of final evaluations)
1. The citation indices of our publications surpass those at other premier research centers forsleep biomedicine, such as the Stanford Center for Sleep Sciences and Medicine.
2.

More senior alumni of the research center have attained independent positions in theacademia and in the industry, both domestic and overseas.

3.

Maintain the current level of research grant acquisition.

（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

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(7) Securing research fundingi) Past record
2007: $8,193,448
2008: $7,244,905
2009: $6,646,950
2010: $10,990,915
2011: $11,240,486(Exchange rate for 1 U.S. Dollar = 80 yen)
The total amount of competitive research funding raised by the prospective Principal
Investigators in the past five years is $44,316,704 averaging at $8,863,341/year.
ii) Prospects after establishment of the center
The University of Tsukuba will be responsible for the labor costs for the scientists who are
full-time Principal Investigators or researchers at the University before participating in this research
center, and for the full-time University staffs who were appointed to the administrative division of thisresearch center. The University will provide support for securing sufficient research space and formoving into new space, and will be partially responsible for providing research funding. By providing
the funding, the University will support the installation of equipment and facilities, renovation ofresearch laboratories, and the administrative management of the research center.
At the time of this application, competitive research funds for 2012 and 2013 have already been
secured through the FIRST program. Applications for other large-scale research grants are in
progress. Considering the level of competitive research funds acquired by the prospective Principal
Investigators in the recent past, we expect that we will be able to secure about the same level ofresearch funds after 2014.
(8) Exploiting the results of previously-initiated center-building efforts (when applicable)
The reason why we believe that this WPI based on our existing FIRST program will succeed
Our forward genetic screening of mutagenized mice for sleep/wake abnormalities, which isenabled by the FIRST program, has been going on smoothly with promising positive results. Our
medicinal chemistry efforts to develop orexin receptor agonists have been progressing as well.
These large-scale projects will yield lots of “seeds” in the near future, from which we will be able todevelop multiple interdisciplinary lines of highly important inquiries. Our suite of cutting-edge
equipment and experimental systems developed under the FIRST program constitute an ideal
environment where the prospective top Principal Investigators of this WPI Center can productively
explore their research ideas.
Our prospects after the FIRST program
Considering the level of competitive research funds acquired by the prospective Principal
Investigators in the recent past, we expect that we together will be able to secure approximately thesame level of external research funds after 2014.
OthersAfter the end of this funding, the University will maintain the research center as a permanentorganization. Administrative procedures that are required for the establishment of a formal research
institute will be complete within this fiscal year. By the end of this funding, the procedures necessary
for the stable operation of the research center even after the end of the program will be complete,such as paying the salaries of multiple Principal Investigators with the University’s budgets.
As for the “ripple effects,” we believe that the concept of creating at Tsukuba an organization,
which is akin to small “departments” in the U.S. universities, as described in the prospective Center
Director’s vision, will have a significant impact on other organizations in Tsukuba and elsewhere.
Specifically, (i) the number of faculty positions is never fixed in advance; when an outstanding faculty（Host institution：University of Tsukuba Center name：International Institute for Integrative Sleep Medicine）

18

candidate is identified, the chairman has the authority to allocate the departmental and other funds inorder to hire him or her in a timely and flexible fashion. (ii) The Principal Investigator’s salary level
would be individually negotiated by the chairman, considering the recruiting situations and his/herprior salary levels, and in accordance of broad guidelines of the institution. (iii) The floor space foreach laboratory within the department would be allocated flexibly and dynamically, considering thelaboratory’s scale of funding, number of personnel, and facility requirements. (iv) A post-doctoralscientist who is deemed capable of conducting scientifically independent research will be provided
with an appropriate position as an immediately independent scientist (who would publish his/herstudies as the corresponding senior author), together with a necessary startup package. (v)Regardless of their age or career stage, all scientists in the department will freely discuss science
with each other, constantly seeking for opportunities for formal and informal cooperation.
The prospective Center Director’s assurance and commitment
Since the start of the current FIRST program at Tsukuba, Yanagisawa has been spending about
50% of the year in Japan, while continuing to hold his UTSW and HHMI positions and operate hislaboratory in Dallas. However, he intends to retire from the HHMI (his sole source of salary) as soon
as possible, and will work full-time as the WPI Center Director, if this application if funded.

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Center Director’s Vision
Chief center-project officer/Center director
Masashi Yanagisawa,
Center for Behavioral Molecular Genetics, Professor- Background, Targets and Objectives
We spend one third of our life in sleep, a behavioral state observed ubiquitously inall mammals and other animal species with well-developed brains, even including
fish and insects. Indeed, sleep is the only physiological state in which a healthy
individual reversibly loses consciousness, posing a great evolutionary risk of being
completely vulnerable and unproductive. Amazingly, however, the fundamental
function of sleep remains unknown. In today’s society, disorder of sleep is not only amajor problem in itself, but a well-recognized risk factor for lifestyle diseases suchas the metabolic syndrome and mental diseases such as mood disorders. Sleep
disturbances can also manifest as a difficult symptom in various neurological andpsychiatric conditions such as dementia and depression. However, because weknow very little about the fundamental mechanisms for sleep regulation, we havevery few means of medical intervention for sleep disturbances. For example, amajority of sleep pills available today all share a single mechanism of action, i.e.
facilitation of the GABA-A receptor. It also remains utterly unknown how sleep
disturbances lead to metabolic dysregulations such as insulin resistance.
Our discovery of the neuropeptide orexin and its prominent role insleep/wakefulness regulation has generated a highly active research field in theneurobiology of sleep and metabolism (our two Cell papers have been cited for>4,300 times combined). Triggered in part by our discoveries, the downstream,
executive neural circuitry and chemistry for the “sleep/wake switch” has been
increasingly revealed in recent years. However, the fundamental governing
principle for the regulation of sleep pressure, i.e., the question of what is the neuralsubstrate for “sleepiness,” whether or not it is localized in the brain, and how it isultimately regulated, remains a mystery. Well-described is the phenomenologicalaspects of sleepiness, with at least three distinct modalities of regulation: i) thecircadian regulation by the internal clock of our brain (sleepiness due to jet lag); ii)
the homeostatic regulation by the history of sleep amounts in the recent past(sleepiness after sitting up all night); and iii) the emotive regulation of arousal(sleepiness forgotten when excited or in emergency). Precise details in themolecular machinery of circadian clocks have been uncovered through intensive
research efforts triggered by the pioneering body of work by Professor Joseph
Takahashi (the proposed head of the U.S. Satellite site in this WPI) and others.
However, the neuronal pathways through which the master clock in the（Host institution：University of Tsukuba

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suprachiasmatic nucleus can eventually regulate sleepiness remain unknown. Even
more frustrating is the fact that the mechanism for sleep homeostasis remains as
one of the biggest black boxes of today’s neuroscience, despite the fact that,phenomenally, it appears to be a deceptively simple negative-feedback system.
I have been convinced that new, highly interdisciplinary approaches are absolutely
required in order to crack open the black box of sleep regulation, and in order todevelop truly new means for controlling sleep and treating sleep disorders. The
present proposal originates from this conviction, which I have attained through morethan a decade of intensive studies since our discovery of orexin. In 2009, I was
selected as one of the Principal Investigators for the FIRST research program
funded by the Cabinet Office of Japan, which helped me setting up a new researchcore at the University of Tsukuba focusing on sleep neurobiology, while
simultaneously retaining my position at the University of Texas Southwestern
Medical Center (UTSW) and the Howard Hughes Medical Institute (HHMI). Alreadyongoing in this FIRST program are intensive interdisciplinary collaborations
spanning such diverse fields as forward genetics, optical neurophysiology andmedicinal chemistry. Many of the proposed PIs in the present application are thesecollaborators through the FIRST program, including Joseph Takahashi(UTSW/HHMI), Takeshi Sakurai (Kanazawa University), Hiroshi Nagase (Kitasato
University), and Satoru Takahashi (University of Tsukuba).
Under this FIRST program, we are currently carrying out a number of ambitious,
long-term projects, including: (1) Large-scale forward genetic screening of randomly
mutagenized mice for sleep/wake abnormalities (collaboration with Takahashi, J.
and Takahashi, S.). We have so far screened ~4,000 mutagenized mice byconducing electroencephalography-based sleep analysis on each mouse, anddetected at least 4 pedigrees of mice exhibiting marked, heritable abnormalities of
sleep/wake patterns. We are now identifying the causative mutations by SNP-based
linkage analysis and whole-exome sequencing. (2) Development of new drugcandidates that target orexin receptors (collaboration with Nagase). At UTSW, wehave screened a library of 250,000 drug-like compounds, and identified several
distinct chemical classes of compounds acting as specific orexin receptor agonists.
Some of them are found to penetrate the blood-brain barrier. Medicinal chemistryefforts are ongoing in order to further optimize these agonists. (3) Real-timevisualization in freely behaving mice of activity patterns of specific neuronal
populations involved in sleep/wake regulation, such as orexin neurons(collaboration with Sakurai). We are pursuing several different optical andelectrophysiological approaches, including the use of a newly developed, fiber-optic
fluorescence endo-microscopy in order to visualize the activity of specificpopulations of neurons located in deep brain structures such as the hypothalamus.
We have already succeeded in optically visualizing the activity of some of these
deep-brain neurons involved in sleep/wake regulation.

（Host institution：University of Tsukuba

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Center name：International Institute for Integrative Sleep Medicine）

The present WPI proposal bases itself upon our ongoing FIRST program. Whilefocusing sharply on the “biomedicine of sleep” as target problem, it will gather top
researchers from a wide range of fields spanning from neurobiology to medicinal
chemistry to clinical-social medicine. By doing so, it will create a new type of
research center at Tsukuba, which is highly visible internationally and sustainable
for long term. If it is funded, I will fully return to Japan and work full time at Tsukuba
as the Center Director. As for its Principal Investigators, in addition to the seven
University of Tsukuba scientists who are internationally recognized for their workthat are closely related to the present objective, we will recruit a number of top
scientists to Tsukuba from the U.S. and from within Japan. The proposal will create
a U.S. Satellite site at UTSW, with the prominent local Principal Investigators whom
I have already been closely collaborating with. My own 20-year tenure at UTSW will
be fully utilized in order to maintain and further our close cooperation. Out of the 12
Principal Investigators who will be working at the Tsukuba site, three will be
foreigners including myself (I am a naturalized U.S. citizen). Including the Satellite
sites, 5 out of the 15 proposed Principal Investigators will be foreigners.

- Creating a new style of research center at Tsukuba by learning from themerits and virtues in the organization of “departments” in major U.S.
universities.
I have had a plenty of opportunities to learn about the merits and demerits of
U.S.-style research organizations and systems. This has been through my 20-year
tenure as a professor at UTSW, one of the best biomedical campuses in the U.S.,
where I have been working also as an HHMI Investigator and serving as an elected
member of the National Academy of Sciences. I believe that we can implement the
WPI’s mission and mandate aiming at “system reform” by selectively learning fromthe merits of departmental organizations and systems in the U.S. academia. For
example, departments would not set fixed a priori the total number of its
tenure-track / tenured professors and other faculty members (e.g., research-trackprofessors); when an outstanding faculty candidate is identified, the chairman has
the authority to allocate the departmental and other funds in order to hire him or her
in a timely and flexible fashion. Selecting and recruiting a faculty candidate would
eventually be done through the authority of the chairman, often being helped by a
departmental recruiting committee, although the decisions would be made only after
thorough discussions among the faculty members of the department as well as
consultations with important researchers outside the department. The researcher’ssalary level would be individually negotiated by the chairman, considering therecruiting situations and his/her prior salary levels, and in accordance of broad
guidelines of the institution. The floor space for each laboratory within thedepartment would be allocated flexibly and dynamically, considering thelaboratory’s scale of funding, number of personnel, and facility requirements.
Capital equipment and large facilities would be shared among the laboratories as（Host institution：University of Tsukuba

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much as practically possible. Supported by the strong commitment from the
President’s Office of the University of Tsukuba, I will aggressively implement thesepractices, which may sound quite usual in the U.S. but not necessarily so in Japan.
One important characteristic of individual laboratories in the U.S. academic
departments is a relatively flat hierarchy among the laboratory members: usually,
there are only two levels (principal investigator / others) or three levels at most(principal investigator / research faculty or senior postdoc / others). In the proposed
Center, I will incorporate these flat personnel structures, especially in order toencourage and develop young independent researchers. Whenever we identify apost-doctoral scientist who is deemed capable of conducting scientificallyindependent research, we will provide him or her with an appropriate position as anindependent scientist (who would publish his/her studies as the corresponding
senior author), together with a necessary startup package. Our proposal includes a
generous amount of fund set aside for this purpose. Regardless of their age or
career stage, all scientists in our Center will freely discuss science with each other,
constantly seeking for opportunities for formal and informal cooperation.

- Fusion of neuroscience and medicinal chemistry
One of the important missions of WPI-Focus is to create new paradigm of researchby the fusion of traditionally separate fields. One such fusion-driven modality thathas been getting a lot of attention in the U.S. in recent years is often called“chemical genetics” or “chemical biology.” Even though Japan’s tradition ofsynthetic organic chemistry excels globally with its breadth and depth, highly
practical aspects of medicinal chemistry has long been considered in Japan an
exclusive domain for the pharmaceutical industry. Never popular in Japan until very
recently has been the idea of carrying out everything in the academia, fromhigh-throughput screening of large-scale compound libraries to medicinal chemistryefforts of optimizing hit compounds, while conducting various in vivo and in vitro
assays. The department where I work at UTSW is, in fact, among the very firstacademic sites to implement serious chemical biology capabilities. It boasts not only
a high-quality, diversity-optimized library of drug-like compounds with sophisticatedscreening robotics, but also a panel of 6-7 expert medicinal chemists as full-time
professors, some of whom recruited from the industry.
In the present WPI proposal, I will recruit our FIRST collaborator Professor Hiroshi
Nagase from Kitasato University to Tsukuba, in order to forcefully propel a fusion ofneurogenetics/physiology and medicinal chemistry. Through his career, Professor
Nagase has created not one but two first-in-class, marketed drug compounds (anorally-active prostacyclin analogue and a kappa-selective opioid receptor agonist) -indeed, a rare achievement as a medicinal chemist. In the proposed WPI Center,（Host institution：University of Tsukuba

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Center name：International Institute for Integrative Sleep Medicine）

multiple efforts of serious and practical medicinal chemistry will be spread out from
Professor Nagase’s laboratory as a core.

- Continuing to provide a research environment and culture where scientists
are encouraged to take “calculated scientific risks”
I am firmly convinced from my own past experiences that truly valuable discoveries
cannot be achieved without taking “calculated risks” in the course of research. In myview, in order to take a calculated scientific risk, a scientist has to carefully consider
the resources available to him/her, incorporate the cutting-edge methodologies ofthe day, and have the “technical courage” of switching the field if necessary. It is a
bitter truth of today’s scientific world that one often has to carry out some lower-riskstudies in order to survive as a professional scientist. However, I believe that our
WPI Center has to keep providing a scientific culture and environment that strongly
encourages all its members, regardless of career stage, to take calculated risks andinitiate “truly interesting” studies.
One example of practical methods to provide such an environment is to facilitate
networking with outside researchers by organizing a regular departmental seminarseries. Having regular, frequent seminars by prominent scientists invited from otherinstitutions is, in my opinion, a salient feature of the departmental system in major
U.S. universities. I have never seen a major academic department in the U.S. that
does not organize a regular departmental seminar series; many larger departments
host weekly seminars. I observe that, unfortunately, such seminars by outsidescientists are much fewer and held only irregularly even in largest universities inJapan. In other words, scientists in Japan pay “seminar visits” to other campuses
much less frequently in general. Importantly, during such visits, the invited speaker
would personally meet with many local faculty members, often including some fromunrelated field. The present proposal takes this problem seriously; we will organizeand host a regular (at least biweekly) seminar series, inviting scientists working in
broadly related fields from within Japan and from abroad. It is obvious that this will
also facilitate the aforementioned training of young scientists to be independent at
early stage, as well as the aforementioned fusion of distinct fields of research. In theend, the proposed Center will aim at providing each independent scientist sufficient
initial resources, as well as support and environment for obtaining further external
resources, so that his/her own scientific ideas are the only bottleneck of research.

- Contributing to the Society
Sound sleep is essential for physical and mental health; deficiencies in the amountand quality of sleep will lead not only to a decrease in higher cognitive functions of
the brain including memory and decision making, but also to an elevated risk for（Host institution：University of Tsukuba

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Center name：International Institute for Integrative Sleep Medicine）

mood disorders such as depression. It is alarming that the lifetime prevalence ofsleep disorders exceeds 30% in industrialized countries. Nocturnal lifestyle oftoday’s society, shift-workers amounting to more than 20% of working population,and steady increase of elderly population all contribute to the problem. Social loss
attributable to sleep disorders is significant, including automotive accidents due toexcessive sleepiness, increase in the prevalence of mood disorders, increase insuicide, and increase in wandering and delirium in elderly patients leading toexcessive loads on caretakers. An ultimate goal of the present proposal isdevelopment of new methods for intervening in sleep disturbances and relateddisorders based on discoveries in the basic research, thereby responding to needsof the society. In order to achieve this, I believe that an aggressive effort for societal
outreach is also essential.

- Concluding remark
I believe that my own mission under this proposal can be summarized as follows:
Fully return to Japan as a full-time Center Director, and create a new “departmental”
site for premiere sleep research at Tsukuba, by learning from the merits of the
U.S.-style academic systems and organizations while retaining the merits of theJapanese tradition (such as the attitude to patiently support long-term projects),
which can only be achieved by fully utilizing over 20 years of my experience as aprincipal investigator in the U.S. academia.

（Host institution：University of Tsukuba

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Center name：International Institute for Integrative Sleep Medicine）

Host Institution’s Commitment
Date November 9, 2012
To MEXT
Host institution University of Tsukuba
Name and title of head of host institution

Nobuhiro YAMADA, President

Signature by
On behalf ofNobuhiro Yamada
President
University of TsukubaJapan
I confirm that the measures listed below will be taken faithfully if the “International Institute forIntegrative Sleep Medicine” is adopted under the World Premier International Research Center Initiative(WPI).
＜Provision in host institution’s mid-to-long-term plan＞
In University of Tsukuba’s Midterm Goals (for the period of April 2010 to March 2016), it isproclaimed that the University shall “strive for deeply specialized expertise, open up new
cross-disciplinary fields, and achieve research results which are outstanding by international
standards over a wide range of academic fields.”
In the University’s Midterm Plan to reach these goals, it is stated that the University shall“promote high quality fundamental research taking a long term view of academic progress andambitiously open up new cross-disciplinary fields,” and “under the leadership of the President carryout research intensively in fields where the University has distinctive capabilities, in particular thosewhich are internationally recognized to have great potential and budding new fields which invite theinteraction of existing fields.”
Therefore, the World Premier International Research Center Initiative (WPI) is in complete
agreement with the University’s Midterm Goals and Midterm Plan.
Further, as the strategy to achieve the University’s goals regarding systems to carry out
research, the Midterm Plan stipulates that “research groups and organizations which are expectedto achieve outstanding research results will be singled out for appropriate support, including
allocation of research resources, hiring of supporting personnel, and reforming of organizations,and will be aggressively promoted as international centers of research.”
In accordance with this Midterm Plan, these research centers will be given the highest priority
in the University’s development efforts. In particular, under the leadership of the President, adeliberative committee preparing for the establishment of the University of Tsukuba International
Institute for Integrative Sleep Medicine (provisional name) has been launched. The whole
University will get involved to make the level of work at this international research center on par withany center in the world.
The first of the Midterm Goals is to make this an “open university” in every aspect, with a“flexible educational and research organization” that is not tied down by past conceptions and thatwill take the lead in promoting “new ventures for the university” that are called for by tomorrow’ssociety.
Our candidate for center director, Dr. Masashi Yanagisawa, has been a professor at the
University of Texas for over 20 years, and will use this experience in managing this center. By
incessantly supporting his efforts, the University will realize the “new ventures for the university”
that are demanded by tomorrow’s society.
（Host institution：University of Tsukuba

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Center name：International Institute for Integrative Sleep Medicine）

We will specify “International Institute for Integrative Sleep Medicine” for a Midterm Plan in thenear future.
＜Concrete Measures＞(1) How it will support the center’s need to secure resources that match or exceed the project grantthrough such means as competitive grants obtained by researchers participating in the project,in-kind contributions and other forms of assistance by the host institution (including partial
payment of salaries, provision of research space), and/or external donations. In the case of
project exploiting previously-initiated center-building efforts, how it will assist the center insecuring sufficient independent resources to continue to secure the same scale of the measured
amount through independent resources after that funding eventually ends.
In order to manage this center and carry out research activities there, the University will give
support as indicated below which will amount to at least as much as the support supplied by the WPI
program. Further, even after the Funding Program for World-Leading Innovative R&D on Scienceand Technology (FIRST Program) ends its “Molecular Mechanism and Control of Complex
Behaviors” project which formed the basis of this center, personnel and laboratory resources will bemaintained at the same level through outside funding to support the participating researchers.
1) The University of Tsukuba Organization for the Support and Development of Strategic Initiatives(formed by the University President and Vice-President) shall continue to give intensive support
to make this an international center pioneering new fields, as one of the Organization’s strategic
initiatives. Specifically, the Organization will support the center with ¥10 million per year to cover
expenses of center activities.
2) Competitive research funds obtained by researchers participating in the center
Competitive research funds obtained by researchers participating in the center amounted to an
average of US$8.86 million in the past 5 years, and it is anticipated that an equivalent amount will
be gained. Even after the completion in FY2014 of the FIRST program that founded this center,
we anticipate that the center will have about 115 researchers who will gain at least the same levelof funds as the previous year. The University will be providing full support for their applications forcompetitive external and internal research funds.
3) Support through handling of personnel expenses
The personnel expenses of University faculty participating in this center will be treated as
University personnel expenses for researchers.
University staff (approximately 3 persons) will be assigned to carry out the chief administrative
work of the center such as general affairs, accounting, and research funding. The expenses forthis staff will be handled by considering them to be administrative staff participating in an
administrative support division.
4) Support through supply of research space
The University will use its good offices to facilitate the building of research facilities (more than
5,000m2) according to a plan that will give the center an outstanding research environment anddistinctive tangible advantages.
5) Support for the use of research facilities
Various core facilities will be offered for use (see paragraph (5) below).
(2) How it will institute a system under which the center’s director is able to make substantive
personnel and budget allocation decisions necessary to implementing the center project—asystem, which in practice, allows the center director autonomy in making decisions regarding thecenter’s operation.
（Host institution：University of Tsukuba

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This center will be established as an independent research organization separate from otherresearch bodies, and also as a special institute for the purpose of making the level of research at thecenter as high as any in the world.
In order for the center director to be able to fully exercise his/her leadership, a system will beinstituted in which the director has managerial powers over key aspects of the center, including thepower to decide upon personnel and the budget. In order to implement this system, the University
will take necessary measures such as amending relevant regulations if needed. Further, the director
will be supported by the administrative division established within this center which includes
Professor Emeritus Katsutoshi Goto who has rich administrative experience such as the director of
the Center for Tsukuba Advanced Research Alliance, administrative personnel dispatched from the
University for support, and personnel recruited from outside the University. These personnel will
supply the director with the information needed for him/her to hand down decisions, and keep thedirector’s work load from becoming excessive.
(3) The support it will provide to the center director in coordinating with other departments within thehost institution when recruiting researchers for the center, while giving reasonable regard to theeducational and research activities of those departments.
The Deliberative Committee to Prepare for Establishment of the University of Tsukuba
International Institute for Integrative Sleep Medicine (provisional name) has been established with
the President as the head and persons in charge of research, administration, finances, and facilities,
University Vice Presidents and Division Directors with international responsibilities, and related
institute directors participating. Necessary adjustments will be made within the University to support
design of the organization of this center.
Further, after the establishment of this center, if persons from other institutes in the University
assemble in this center as principal investigators, thorough adjustment will be made with thoseinstitutes in keeping with this center’s status as a target for the Organization for the Support andDevelopment of Strategic Initiatives.
Specifically, adjustment and support will be carried out so that there is no impediment to theresearch and education carried out by the institute in question; these support includes securing
replacement personnel and taking measures to reduce administrative and educational work loads.
Further, a place for interchanges with the researchers at this center will be created, so as to aid in
the nurturing of outstanding new personnel.
(4) Its flexibility in applying, revising, or supplementing the host institution’s internal systems asneeded for the center to effectively implement new management methods (e.g.,
English-language environment, merit-based pay, top-down decision making) unfettered byconventional modes of operation.
This center shall be made an independent research organization reporting directly to the
University President and kept separate from other research centers. University systems will be
executed flexibly, making amendments and adjustments as necessary.
Specifically, English shall be the official language of the center, with the administrative tasks
carried out in English and administrative documents made bilingual. Persons with high English
proficiency will be recruited from within and outside the University, and further training will be
provided to those persons after entering the center.
Under the management of the director, systems for determining salaries based on merit, forannual salaries, for evaluating researcher’s achievements, for determining salaries based on
evaluations of the work, and for renewal of contracts will be introduced.
（Host institution：University of Tsukuba

3

Center name：International Institute for Integrative Sleep Medicine）

Also, to deal with requests for flexible execution, improvement, or adjustment of systems in thecenter, the director will exercise the functions established by the Organization for the Support andDevelopment of Strategic Initiatives for dealing with research groups to take appropriate measures,subject to amendment through negotiation with the University President and related Vice Presidents
and administrative divisions.
(5) Its accommodation of the center’s infrastructural requirements (for facilities, e.g., laboratory
space; equipment; land, etc.).
In order to assemble many leading researchers by making the center the one place where theywant to work, the University will use its good offices to the greatest extent to facilitate the building ofresearch facilities according to a plan that will give the center an outstanding research environmentand distinctive tangible advantages so that it can claim with confidence to be a place for research of
the highest level.
Specifically, the center will be provided with all floors on the E Building of the University
Hospital, which will be vacated by January, 2013 into the new ward building currently underconstruction. The center will continue to use the floors on the Health and Medical Science Innovation
Laboratory that are currently occupied by the FIRST Program. Together, the center will be provided
with more than 5,000 m2 of research floor space. The Hospital E Building is located in close
proximities to both the Innovation Building and the Laboratory Animal Resource Center, whichshould be highly advantageous for the center to facilitate its research. During the required
renovation of the E Building, the center will be provided with temporary floors on the Laboratory of
Advanced Research D.
The Research Facility Center for Science and Technology will assist persons wishing to use
facilities in and outside the University, through the Open Facility function which is scheduled to start
being offered sometime this fiscal year. Among these facilities are those for cutting-edge mass
spectroscopy, super-high resolution ultrasound echo sonography for mice, and in vivo
luminescence/fluorescence imaging system for mice. This function will be expanded in stages, andwill make possible the use of the pioneering research facilities in the Tsukuba area.
Further, University of Tsukuba will provide university housing or satisfactory housing close to
the University to researchers and administrative staff participating in this center, including foreign
researchers. The University will also make its housing facilities available to foreign and Japanese
researchers visiting this center so that they can hold seminars and carry out joint research.
(6) How it will support to sustain the center as a world premier international research center after the
WPI-grant period ends.
As a concrete policy for raising the level of research to the highest international level, a goalproclaimed in the University’s Midterm Plan, it is stated in this Plan that the University shall “promotehigh quality fundamental research taking a long term view of academic progress” and that “researchgroups and organizations which are expected to achieve outstanding research results will be singled
out for appropriate support, including allocation of research resources, hiring of supporting
personnel, and reforming of organizations, and will be aggressively promoted as international
centers of research.” The measures necessary to make this one of the world’s leading centers, ofwhich the University may be proud, shall be taken.
(7) Other types of assistance it will provide to give maximum support to the center in achieving its
concepts and objectives and becoming a world premier international research center in both nameand deed.
The University of Tsukuba is striving to be an “open university,” and is leading the way inrealizing a flexible education and research organization and the new university organization（Host institution：University of Tsukuba

4

Center name：International Institute for Integrative Sleep Medicine）

demanded by tomorrow’s society. With this as the conceptual basis of our policies, we haveintroduced reforms in Japan’s universities. Dr. Sin-itiro Tomonaga, Dr. Leona Esaki, and Dr. Hideki
Shirakawa are Nobel prize Laureates associated with the University, and in recent years, two of thecenters of the Funding Program for World-Leading Innovative R&D on Science and Technology(FIRST Program) created by the Japanese government are being run in the University.
Also, in order to make the University more international, it is one of 13 universities promoting theformation of a network, Global 30, that will make international interactions a part of daily activities,
and that will make the University into a world center of knowledge.
A University of Tsukuba research administrator (URA) headquarters (headquarters chief: theVice President in Charge of Research) which is charged with carrying out business involving the
URAs who are sent from the Ministry of Education, Culture, Sports, Science and Technology will
provide support for research strategies, international joint efforts, compliance with legal andsocial requirements, etc. that are key to this center’s research activities.
In order to truly raise the research level of this center as high as any in the world, the know-how
and resources which can be the basis of such accomplishments must be exploited to the maximum
extent. It is the responsibility of the University to see that this is carried out, by supplying allnecessary support.

（Host institution：University of Tsukuba

5

Center name：International Institute for Integrative Sleep Medicine）

(Appendix 1)

List of Principal Investigators

Name

Age

1

Masashi Yanagisawa*

52

2

Hiromasa Funato*

43

3

Takeshi Sakurai*

48

4

Yoshihiro Urade*

59

5

6

7

8

9

10

Robert Greene*

Qinghua Liu*

Hiroshi Nagase*

Ichiyo Matsuzaki*

Hitoshi Shimano*

Junichi Hayashi*

Current affiliation(organization,
department)
University of Tsukuba,
International Institute forIntegrative Sleep
Medicine
University of Tsukuba,
International Institute forIntegrative Sleep
Medicine
Kanazawa University,
Department of
Physiology and
Neuroscience
Osaka Bioscience
Institute, Department of
Molecular Behavioral
Biology

Academic
degree andcurrent
specialties

Notes

M.D.,Ph.D.
Neuroscience,
Pharmacology
M.D.,Ph.D.
Neuroscience

M.D.,Ph.D.
Neuroscience

By the end of 2012

Ph.D.
Neuroscience,
Biochemistry

By October 2013

62

University of Texas
Southwestern Medical
Center,
Department of Psychiatry

M.D,Ph.D.
Neuroscience

By October 2013

41

University of Texas
Southwestern Medical
Center,Department ofBiochemistry

Ph.D.
Biochemistry
Molecular biology

By October 2013

65

University of Kitasato,
Department of Medicinal
Chemistry and School of
Pharmacy

Ph.D.
Medicinal
Chemistry

By October 2013

52

University of Tsukuba,
Faculty of Medicine

M.D,Ph.D.
Occupational
Psychiatric Medicine,Space Medicine

51

University of Tsukuba,
Faculty of Medicine

M.D.,Ph.D.
Endocrinology,
Metabolism

63

University of Tsukuba,
Faculty of Life andEnvironmental Sciences

Ph.D.
Cell Biology（Host institution：University of Tsukuba

1

Center name：International Institute for Integrative Sleep Medicine）

(Appendix 1)

List of Principal Investigators

Name

11

12

13

14

15

Akiyoshi Fukamizu*

Satoru Takahashi*

Tetsuo Shimizu*

Carla Green*

Joseph Takahashi*

Age

Current affiliation(organization,
department)

Academic
degree andcurrent
specialties

53

University of Tsukuba,
Faculty of Life andEnvironmental Sciences

Ph.D.
Molecular
Biology

51

Uiversity of Tsukuba,
Faculty of Medicine

M.D.,Ph.D.
Developmental
biology

59

Akita University Graduate
School of Medicine,
Department of
Neuropsychiatry

M.D.,Ph.D.
Psychiatry

satellite

50

University of Texas
Southwestern Medical
Center, Department of
Neuroscience

Ph.D.
Neurosciencesatellite (overseas)

61

University of Texas
Southwestern MedicinalCenter, Molecular
Neurobiology and Genetics

Ph.D.
Neurosciencesatellite (overseas)（Host institution：University of Tsukuba

2

Notes

Center name：International Institute for Integrative Sleep Medicine）