The aim of this R&D area is to create breakthrough technology platforms based on biomolecular dynamics analysis, the outcomes of which will contribute to medical applications such as drug discovery, disease diagnosis, and prevention. The technology platforms should increase the capacity of current systems to find, identify, and quantify disease-related metabolites and their associated factors as potential target molecules for disease control and broader medical applications.In particular, metabolomics and other “omics” approaches are in great demand for the identification of disease-associated factors; therefore, these need to be developed. Further, we need the technology to identify proteins and other biomolecules related to these factors so they are within the scope. By combining biomedical research projects with the newly developing technology platforms, this R&D area aims to deliver proofs of concept for human disease control by taking full advantage of information obtained about core biomolecules as potential targets for medical applications.The technical goals specified by the R&D area should be shared among individual research projects. Therefore, the management strongly encourages them to collaborate with others within this so-called virtual-network-type institute as well as with projects in the corresponding Precursory Research for Embryonic Science and Technology (PRESTO) Research Area (of the Japan Science and Technology Agency (JST)), both aiming for the establishment and sophistication of technologies in a team-oriented manner. The management also prioritizes smooth translations to clinical applications; therefore, it considers further efforts allied with other drug discovery programs.

Program Supervisor (PS)

SHIMIZU Takao Project Leader, Department of Lipid Signaling, National Center for Global Health and Medicine

Creation of Innovative Technology for Medical Applications Based on the Global Analyses and Regulation of Disease-Related Metabolites

【Research and Development Objectives】Creation of core technologies for early-stage drug discovery through the investigation of disease-specific profiles of biomolecules

Disease-Related Metabolites

57

R&D Area Advisors

ABE Keiko Professor, Graduate School of Agricultural and Life Sciences,

The University of Tokyo

UEMURA Daisuke Distinguished Professor,

Kanagawa University

ODA Yoshiya Professor, Graduate School of

Medicine Lipidomics,The University of Tokyo

SATO Taka-aki Fellow, Director of Life Science

Research Center, Shimadzu Corporation

SUZUKI Rami Vice President Head,

Medical Affairs Division,Janssen Pharmaceutical K.K.

TAKAI Yoshimi Professor, Graduate School of

Medicine, Kobe University

TAKAGI Toshihisa President, Toyama University of

International Studies

NARUMIYA Shuh Professor and Director,

The Medical Innovation Center Graduate School of Medicine,

Kyoto University

NAGANO Tetsuo Visiting Professor / Emeritus Professor,

Drug Discovery Initiative, The University of Tokyo

NISHIJIMA Masahiro Professor emeritus,

Showa Pharmaceutical University

MATSUZAWA Yuji Director Emeritus . Supreme Adviser,

Sumitomo Hospital

Development of fundamental technologies for medical applications based on membrane phospholipids

ARAI Hiroyuki Professor, Graduate School of Pharmaceutical Science, The University of Tokyo

More than a thousand different phospholipid species are present in tissues and cells. In addition to their role as a building block of biological membrane, phospholipids are now recognized as important players in the regulation and control of cellular physiologies and diseases. In this study, we will focus on metabolic syndrome and cancer, and develop the innovative technologies that accelerate the researches for disease-associated membrane phospholipid metabolites and their target proteins. We will also aim to provide biomarkers and therapeutic targets for these diseases.

Identification of disease-related lysophospholipid and its application to medical science

AOKI Junken Professor, Graduate School of Pharmaceutical Science, Tohoku University

It has been revealed that lysophospholipids have pivotal role in both physiological and pathological conditions as so-called second-generation lipid mediators. They include lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P) and lysophosphatidylserine (LysoPS). In this study we try to identify disease-related lysophospholipids by determining the lysophospholipid level in various clinical samples using a mass spectrometry with high sensitivity. We also apply these disease-related lysophospholipids to the identification of biomarkers and the drug discovery, thus contributing to medicine and health care.This project was completed in advance of planned, when was selected as a LEAP project.

Formulation of a hub for metabolome analysis and development of medical basic technologies based on cancer specific metabolism

SOGA Tomoyoshi Professor, Institute for Advanced Biosciences, Keio University

We develop a cutting edge metabolomic analysis technology, which enables highly sensitive, quantitative and simultaneous analyses of thousands of metabolites in tissues and cells. Using the approach, we reveal cancer specific metabolism and develop medical basic technologies for anti-cancer drug screening and cancer diagnostic imaging.

Development of basic technology for identification of bioactive metabolites and target proteins

SODEOKA Mikiko Chief Scientist, Synthetic Organic Chemistry Laboratory, RIKEN

We will develop screening system based on synthetic organic chemistry, Raman spectroscopy, and mass spectroscopy. This screening system will use a probe molecule with tiny tag, and the tagged molecules or peptides will be searched from a complex mixture guided by their Raman scattering peaks. Synthetic methods of the probe molecules as well as new chemical methodologies for the screening will be also developed. By using this new system, we will challenge the determination of target protein and binding site of bioactive small molecules as well as identification of unknown metabolites.

Development of user-friendly metabolomics technology for application to lifestyle-related diseases research

FUKUSAKI Eiichiro Professor, Graduate School of Engineering, Osaka University

Metabolomics is a comprehensive analysis based on total profiling of whole metabolites. Metabolomics is expected as a key technology for various clinical researches. The present study aims to develop a user-friendly metabolomics technology by which clinical researcher can operate metabolomics research without the assistance of skilled persons. The novel technology will be applied to “Pathological association analysis of “diabetes / metabolic syndrome / periodontal disease / atherosclerosis” and “Screening of biomarker for chronic inflammation derived from periodontal disease”.

FunctionalIm

pairment

Mechanobiology Microbiom

eLipid

Molecules Disease-Related

MetabolitesHom

eostasisLEAP

Completed

Early Life StageAdaptation / repair

Started in 2013

Started in 2014

58

Chemical biological exploration of new functions of endogenous lipid-related molecules

UESUGI Motonari Professor, Institute for Chemical Research, Kyoto University

Endogenous lipid molecules often have cryptic biological activities yet to be identified. Disclosure of these new activities, identification of the molecular targets, and their specific chemical modulation would contribute to both basic biological research and drug discovery.Preliminary studies suggest such new functions of vitamin D derivatives and acyldopamins. This CREST project focuses on their molecular understanding and synthetic modulation with the goal of providing novel pharmacological approaches to treating metabolism disorders and cancers.

Creation of search techniques for disease-related metabolic activities based on live imaging of clinical specimen and its application to drug developments

URANO Yasuteru Professor, Graduate School of Pharmaceutial Sciences, The University of Tokyo

In this project, a large chemical library composed of various chemistry-based fluorescence probes will be developed for visualizing metabolic activities of living cells, by fully utilizing our rational molecular design strategies. This fluorescence probe library will be applied to fresh human clinical specimens of cancers and arteriosclerosis to unveil disease-related metabolic activities. Based on the obtained results, novel imaging drugs and tools for ultra-early diagnosis of diseases, as well as novel highly efficient therapeutic drugs with minimal side-effects will be developed, which will realize innovative medical technologies and will facilitate the integration of diagnosis and therapy.

Establishment of the platform for the control and prevention of allergy by omics-based understanding of its pathogenesis

OHNO Hiroshi Team Leader, Center for Integrative Medical Science, RIKEN

Allergic diseases is steadily increasing in recent years. It is believed that allergy will develop by the combination of genetic factors and environmental factors; for the latter, attention has been focused on the importance of metabolites and biologically active substances produced by intestinal microbiota, as well as in breast milk. In this study, we aim to identify potential biomarkers for allergy-developing/aggravating factors, with particular emphasis on the lipids by high-precision and cyclopedic omics analysis of metabolites and physiological active substances in breast milk and intestinal microbiota.

PLA2 metabolome-based identification of novel lipid-metabolic maps linked to diseases from bench to clinic

MURAKAMI Makoto Professor, Faculty of Medicine, Center for Disease Biology and Integrative Medicine, The University of Tokyo

Lipid biology has currently been based on studies of individual biosynthetic enzymes or receptors, yet the whole view of lipid-metabolic flows that underlie various diseases still remain incompletely understood. Taking advantages of gene-manipulated mice for a full set of phospholipase A2s as well as downstream enzymes and receptors, in combination with lipidomics, single cell technology and structural biology, this study aims to identify novel lipid-metabolic pathways that are lined to diseases, and thereby to provide rationales for novel therapeutic strategies to control the diseases by targeting the specific lipid pathways.

Development of a novel medical application by systematic mining of metabolism regulator molecules

KABE Yasuaki Associate Professor, School of Medicine, Keio University

Some metabolites showing dramatic changes under disease conditions do not only serve as disease markers but exert their potent biological actions to regulate metabolic systems as a whole. However, the relationship between such metabolites and their target macromolecules remain unknown largely. This project aims to reveal unravelled actions of metabolites and their receptors using multidisciplinary approaches and advanced technology, thereby developing medicines to treat diseases with unmet needs.

Disease-Related Metabolites

Started in 2014

59

How gut microbiota shifts metabolites leading to neuro-endocrine disorders in mouse and man

FAGARASAN Sidonia Team Leader, Center for Integrative Medical Science, RIKEN

More than 1000 bacterial species (at densities that exceeds 12 power of 10 per 1 gram of intestinal content) make an additional internal organ called microbiota. The composition of microbiota is heavily influenced by the immune system. In its turn, the microbiota influences the function of major physiological systems-like digestive, neuroendocrine and higher brain functions likely through the metabolites they produce or regulate. We aim to understand how changes in metabolites caused by alterations of microbiota due to improper function of immune system leads to development of metabolic and brain disorders.

Cancer diagnosis/drug efficiency evaluation biomarker research by comprehensive metabolomics/targeted proteomics and establishment of innovative integrated clinical diagnosis network

YOSHIDA Masaru Associate Professor, Graduate School of Medicine, Kobe University

In this study, we search the protein/metabolite biomarkers for cancer diagnosis and drug efficiency evaluation/toxicity prediction by using high quality clinical samples that are collected on the basis of ‘Standard Operating Procedure’, and next validate their biomarkers. Moreover, we develop the medical devices to measure the biomarkers found in our study. Then, we establish the medical cloud system innovative integrated clinical diagnosis network, and next lead to development of the new model for next generation diagnosis system.

Development of metabolite biomarkers of Parkinson’s disease and identification of drug seeds from chemical screening based on the biomarkers

HATTORI Nobutaka Professor and Chairperson, Graduate School of Medicine, Juntendo University

Increase of number of patients with Parkinson’s disease (PD) causes increment of medical and nursing costs because of the rapid population ageing in Japan. In this study, we try to develop serum metabolite biomarker(s) of PD patients to make accurate differential diagnosis as well as disease-grading possible with metabolomics techniques. Also, to figure out the relationship of the identified biomarker(s) with disease pathogenesis, we perform confirmation studies with DNA/RNA, disease models of mice and neurons differentiated from induced pluripotent stem cells. Likewise, chemical screening is performed to identify drug seeds to correct the biomarkers, leading to modification of the disease course.

FunctionalIm

pairment

Mechanobiology Microbiom

eLipid

Molecules Disease-Related

MetabolitesHom

eostasisLEAP

Completed

Early Life StageAdaptation / repair

60