R&D Area Advisors

IRIKI Atsushi Team Leader, RIKEN Center for

Biosystems Dynamics Research

OHSHIMA Etsuo Representative Director and

President & CEO, Kyowa Pharma Chemical Co., Ltd.

KANGAWA Kenji Emeritus Director General,

National Cerebral and Cardiovascular Center Research Institute

KOJIMA Itaru Professor, Gunma University

SAKAGUCHI Shimon Professor, Osaka University

SAKATA Tsuneaki Senior Fellow, Shionogi & Co., Ltd.

SUNAGAWA Kenji Director, Circulatory System

Research Foundation

NAGASE Miki Professor, Kyorin University

MOCHIZUKI Atsushi Professor, Institute for Frontier

Life and Medical Sciences, Kyoto University

NAKAO Kazuwa Professor (Special Appointment),

Kyoto University

NABESHIMA Yo-ichi Director, IBRI,

Foundation for Biomedical Research and Innovation at Kobe

The objective of this R&D area is to comprehend the process from birth to demise, which takes place in the individual, from the view of a dynamic homeostatic mechanism and to elucidate

the mechanisms as to how the individual adapts and changes in reaction to internal and external stresses in a spatio-temporal and cross-sectional manner. The dynamic homeostatic mechanism is operated via a high-order network consisting of the nervous, immune, endocrine, circulatory, and other systems. Furthermore, we aim to understand various diseases, including lifestyle diseases, as deviations from or breakdown of a “homeodynamic” state, constituting a ground for the development of preventive technologies that predict and control such deviation.Particularly in recent years, technologies such as development of cell-specific genetically modified animals and cell separation technologies have made great progress and they have triggered major changes in life science and medicine. Expectations are to gain a better understanding of mechanisms of homeostasis and adaptations to various stressors, which function through interactions between different cells, systems, and organs. Furthermore, advances in life science and clinical medicine that control these mechanisms are needed. Specifically:1. How complex functional networks behave interdependently in order to maintain homeostasis in response to external and internal stresses will be elucidated. These networks correlate among multiple organs, such as between parenchyma cells and interstitial cells, among organs as well as among the systems like the nervous, immune, endocrine, circulatory and others. In particular, humoral factors, neurotransmission, immunocytes, and interstitial cells that are involved in the maintenance and dysfunction of homeostasis need to be identified. These findings are needed to develop technologies that can be used to control homeostasis.2. Researchers are expected to elucidate the phases of sequential and dynamic changes that take place in an individual’s homeostatic mechanism during the life stages through birth, growth, development, and aging. Technologies that enable early detection of the subtle symptoms of these phases, as well as those to control them, are to be developed.3. This R&D area involves research aiming at elucidation of the mechanisms in onset and progression of organ dysfunction resulting from internal and external factors, the biological defense mechanisms against stresses and injuries and healing mechanisms. Furthermore, we aim to develop technologies that will assist in the diagnosis and treatment of human patients. We will apply results of basic research for examination in clinical cases as much as possible, and investigate the potential of medical care where multiple medical departments cooperate based on new concepts of pathology.4. We aim at the establishment of highly reliable methods to control these networks, based on multilateral understanding of the dynamic interactions between these complex networks. To achieve this goal, we will work to promote simulation technologies and theoretical computational science research that would make these technologies possible.Through this research, we will elucidate previously unknown molecular, cellular, and networking mechanisms and develop new medical technologies based on these understandings.

Program Supervisor (PS)

NAGAI Ryozo President, Jichi Medical University

Innovation for Ideal Medical Treatment Based on the Understanding of Maintenance, Change and Breakdown Mechanisms of Homeostasis among Interacting Organ Systems

【Research and Development Objectives】Integrated clarification of the maintenance and change mechanisms of dynamic homeostasis in the body and creation of technology to understand and regulate complex dynamic homeostasis to achieve preventive medicine, appropriate diagnosis and treatment

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Holistic investigation of the inter-organ communication systems responsible for metabolic homeostasis and disorders

KATAGIRI Hideki Professor, Tohoku University Graduate School of Medicine

We have discovered several neuronal relay systems responsible for inter-organ metabolic communication to maintain systemic homeostasis in multi-organ organisms including humans. Based on our original discoveries, we will investigate the mechanisms underlying coordinated regulation of metabolism in different organs/tissues by the brain and the roles of inter-organ metabolic communication in obesity- and aging-related metabolic disorders. In addition, using human samples, we will examine whether these systems functionally works in human subjects and search for chemical reagents which can control these systems. These investigations are anticipated to provide potential targets for developing preventive and therapeutic strategies.

Elucidating the pathophysiology of senescence-associated homeostatic disorders and its control

HARA Eiji Professor, Research Institute for Microbial Diseases, Osaka University

Cellular senescence is the state of irreversible cell cycle arrest that can be induced by a variety of potentially oncogenic stimuli and has therefore long been considered to suppress tumorigenesis, acting as a guardian of homeostasis. However, surprisingly, emerging evidence reveals that senescent cells also promote secretion of various inflammatory and pro-proliferative factors, all of which are associated with homeostatic disorders such as cancer, atherosclerosis or osteoporosis. It is therefore quite possible that accumulation of senescent cells during the aging process in vivo may contribute to age-related increases in homeostatic disorders. In this study, we aim to clarify the molecular mechanisms linking cellular senescence and homeostatic disorders and to develop novel therapeutic strategies for aging-associated diseases.

Mechanisms of homeostatic maintenance by quorum control of the tissue in whole body

MIURA Masayuki Professor, Graduate School of Pharmaceutical Sciences, The University of Tokyo

Cell number of the tissue is tightly regulated and this regulation is crucial for homeostatic maintenance of the body. Regulatory mechanisms of the tissue quorum are thought to be based on the communication between dying cells and proliferating cells in whole body. In this research, we will explore the basic mechanisms of the tissue quorum control not only in the tissue but also in whole body. Our research will contribute to clarify the common mechanisms of cancer or degenerative diseases in which the tissue quorum is dysregulated. Our research goal will also facilitate the development of new diagnosis and treatment of diseases.

Discovering therapies for intractable diseases through the identification and characterization of gut microbiota

HONDA Kenya Professor, Keio University School of Medicine

The mammalian alimentary tract harbors over thousand of species of commensal microorganisms that homeostatically interact with the host. In this study, we focus on immunological attributes of the microbiota and identify responsible bacterial species and factors for shaping the immune system. We aim to develop a way to manipulate the microbiota for many mucosal immune conditions, such as inflammatory bowel diseases (IBD) and allergy.

This project was completed in advance of planned, when was selected as a LEAP project.

Study of autophagy toward development of therapy for disorders caused by hypernutrition

YOSHIMORI Tamotsu Professor, Graduate School of FrontierBiosciences, Osaka University

Hypernutrition disturbs physiological homeostasis maintained by a coordinated network of endocrine, metabolic, and immune systems, which causes obesity-related diseases including diabetes and elevated risk of infection. The multi-organ network is maintained by autophagy, an intracellular cleaning system and its activity is down or falls short by hypernutrition-caused stresses. In this study, we aim to unravel mechanisms underlying collapse of homeostasis caused by autophagy dysfunction under hypernutrient condition and develop new therapeutic strategy for obesity-caused diseases based on autophagy regulation.

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Early Life StageAdaptation / repair

Started in 2012

Started in 2013

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Clarifying and controlling the pathology of lifestyle diseases caused by alteration of homeostatic maintenance based on tissue repair

OIKE Yuichi Professor, Graduate School of Medical Sciences, Kumamoto University

Stresses derived from aging and lifestyle changes cause tissue damages. These damages are generally repaired by homeostatic mechanisms, in which various types of cells react to stresses and promote tissue remodeling through intercellular communication, thereby maintaining tissue homeostasis. However, alteration of these mechanisms leads to the pathologic tissue remodeling and results in pathogenesis and progression of lifestyle diseases. In this study, we aim to clarify the molecular mechanisms underlying pathogenesis and progression of lifestyle diseases from point of view of “crosstalk between tissue repair and immune response” and to develop novel preventive, diagnostic, and therapeutic strategies for lifestyle diseases.

Homeostatic regulation by bones through the inter-organ metabolic network

SATO Shingo Junior Associate Professor, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences

It has been revealed that bone is not just a passive organ working against gravity, but, indeed, an active organ affecting whole-body energy metabolism. In this project, we will further develop our recent discovery that bone and central nervous system communicate with each other: we will address the molecular basis for the inter-organ metabolic network, such as brain, fat and kidney, with a focus on bone as a hub. We aim to elucidate a molecular mechanism for maintaining whole-body homeostasis in multi-organ animal and develop a novel preventive and therapeutic approach for bone degenerative disease and metabolic disease.

Identification of novel scavenging system in organisms and its therapeutic application

MIYAZAKI Toru Professor, Faculty of Medicine, The University of Tokyo

A variety of biological garbage such as necrotic, cancerated, or degenerated cells, are constitutively induced in our body due to both physiological and pathological events. Such undesired substances are usually eliminated quickly, which is followed by the restoration of tissues. Thus, this scavenging response is essential for maintaining the homeostasis of the body. Although the presence of scavenging system is well accepted based on the identification of multiple scavenger receptors, the machinery that distinguishes the garbage and normal cells remains largely unknown. In this project, we will first focus on this discriminating mechanism and identify the responsive molecules. Secondly, we will clarify the association of the unbalanced discriminating/scavenging system with types of diseases. Thirdly, we will develop diagnostic and therapeutic application of the newly identified elements against multiple incurable diseases.

Understanding homeostatic mechanisms maintained by the cardio-osteo-renal network and interconnecting blood vessels

MOCHIZUKI Naoki Director General, National Cerebral and Cardiovascular Center Research Institute

We have identified a secretary molecule from the zebrafish embryonic hearts which might potentially regulate cardiogenesis and osteogenesis; therefore we name this molecule “heart-derived osteogenesis inducing molecule (HDOCI).” In this project, our team aims at clarifying the roles for HDOCI in homeostatic control among heart, bones, and kidneys using zebrafish and mice as models in which genes of our interests are genetically modified. We plan to explore the inter-organ regulation initiated by HDOCI. Furthermore, to examine the clinical relevance of HDOCI, we will investigate whether it becomes a potential biomarker for certain diseases and test whether it will be used for treatment of bone or heart diseases.

A challenge to reveal dynamic properties in circadian sleep-wake homeostasis

UEDA Hiroki Professor, Graduate school of Medicine, The University of Tokyo

The aim of this study is to reveal mechanisms that maintain dynamic homeostasis in the living systems. We choose the mammalian sleep-wake homeostasis as a model system and investigate how the average (diurnality or nocturnality), the dispersion (the length of sleeping time), and the amount (insomniac or hypersomniac responses) of sleep during circadian time are determined by environments and history of activities. For this purpose, we apply developing technologies for organism-level systems biology and execute a comprehensive study to examine dynamic properties of the biological system inside cell-to-tissue scale, and their relations to organism-level phenotypes.

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Started in 2013

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Phosphatostasis and phosphatopathy: pathophysiology of the inter-organ network maintaining phosphate homeostasis

KURO-O Makoto Professor, Center for Molecular Medicine, Jichi Medical University

Phosphate homeostasis is maintained by a balance between dietary intake, urinary excretion, and bone deposition. This process requires inter-organ communication between intestine, kidney and bone mediated by humoral factors like calciprotein particles (CPPs). CPPs are colloidal nanoparticles of calcium phosphate crystals and function as cargos delivering ingested phosphate to the bone. However, CPPs increase upon chronic kidney disease and behave like a pathogen that induces non-infectious inflammation and accelerates aging. The purpose of this project is to understand CPP function in health and disease, which may help identify new diagnostic and therapeutic targets for aging and chronic kidney disease.

Homeostatic regulation and dysregulation of neural stem cells under physiological and pathological challenges

GOTOH Yukiko Professor, Graduate School of Pharmaceutical Sciences, The University of Tokyo / Principal Investigator, International Research Center for Neurointelligence (IRCN), The University of Tokyo

Accumulating evidence indicates that newborn neurons in the adult brain contribute to various cognitive functions as well as stress responses. We have identified an embryonic “origin” cell population that later become adult neural stem cells. In this project, we aim to elucidate the mechanisms by which these “origin” cells are established during embryonic development and maintained until the adult stage, and how stress and other insults may perturb these processes. This study may provide a clue to understanding mental disorders and their therapeutic development.

A novel approach to drug discovery through receptor activity modification

SHINDO Takayuki Professor,Faculty of Medicine, Shinshu University

Bioactive humoral molecules play central roles in the regulation of homeostasis as the method for communication by cells and organs. On the other hand, cells and organs have control system for the information transmitted by the bioactive molecules. In this study, we will clarify the mechanism of homeostasis regulated by “RAMP system”, which works as the major control system for information of bioactive molecules. We will apply the research results to the drug discovery for lifestyle-related diseases.

Understanding the autonomic nervous system underlying the gut-brain axis: with a view to exploring higher-order homeostatic mechanisms

TAKAHASHI Yoshiko Deputy Executive Vice-President, Professor, Graduate School of Science, Kyoto University

The gut in our body strongly maintains homeostasis, and digests food and absorbs nutrients steadily irrespective of environmental changes to which it is exposed. Disruption of the gut homeostasis by stress or other stimuli is thought to cause a variety of gut disorders including irritable bowel syndrome. The exact cause of these disorders, however, remains unknown. In this project, we aim to elucidate the functional connectivity between the gut and the central nervous system (gut-brain axis) by examining the autonomic nervous system, and to obtain vital knowledge toward the development of new strategies for treating gut homeostasis-related disorders.

Regulatory mechanism underlying tissue fibrosis induced through local cell-cell interaction and systemic organ network and its medical applications

OGAWA Yoshihiro Professor, Graduate School of Medical Sciences, Kyushu University

Tissue fibrosis, a common feature of chronic inflammatory diseases, may often result in the malfunction of a variety of organs and eventually organismal death. This study is designed to elucidate the molecular mechanism underlying tissue fibrosis, which occurs through the dysregulation of homeostatic mechanisms; local cell-cell interaction and systemic organ network. Accordingly, we wish to identify novel biomarkers and drug targets against non-alcoholic steatohepatitis (NASH), which may lay the groundwork for its preemptive medicine and innovative anti-fibrotic strategies.

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Early Life StageAdaptation / repair

Started in 2014

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Signal transduction systems responsible for tissue, organismal and transgenerational homeostasis

NISHIDA Eisuke Director, RIKEN Center for Biosystems Dynamics Research

In this study, we are analyzing signal transduction systems that are responsible for tissue, organismal and transgenerational homeostasis. We aim to identify novel signaling molecules, signal transduction pathways, or their crosstalks by using several tissues in multiple model organisms through utilizing our capacity and experiences in studies on the mechanisms and functions of intracellular and intercellular signal transduction pathways.

Investigation of energy metabolism and immune system based on the association with autonomic nerve and peptides

NAKAZATO Masamitsu Professor, Department of Internal Medicine, University of Miyazaki

Signals to regulate food intake and energy metabolism, which are derived from the peripheral organs, are transmitted to the hypothalamus via the afferent autonomic nerves. The brain regulates whole body organs, immune system, blood vessel tone and metabolism in the skeletal muscle via the efferent autonomic nerves. In this study, we aim to identify novel peptides involved in the signal transduction related to energy metabolism by the autonomic nerve. We also aim to understand the concerted control system among the autonomic nerve, endocrine and immune systems and substances functioning in these systems, and further pathophysiology of impairment of energy homeostasis, such as obesity and cachexia.

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Early Life StageAdaptation / repair

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