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Understanding and medical application of proteostasis

1. Overview

With the recent development of genome analysis technology, the relationship between various diseases and gene mutations has become clear, but there are still many diseases of which the molecular mechanism leading to the onset is unknown. Many cohort studies have found cases in which disease-related genes do not necessarily cause disease. In future disease studies, it is necessary to deepen the understanding of the process of post-translational modification (glycosylation, oxidation, glycation, etc.) and the control of translation, in addition to the analysis of expression of gene and protein. However, research on proteins, which are structurally diverse and alter their structure and function with post-translational modifications in response to the surrounding environment, has lagged behind research on nucleic acids, which have relatively simple structures and are easy to handle.
This research and development objective aims to clarify the structural and functional relationships of proteins through biochemical and structural biological approaches to protein homeostasis (proteostasis*), denaturation, aggregation, and degradation of proteins that cause an irreversible reaction, and post-translational modifications that have an irreversible effect on protein function, in order to create seeds that will contribute to the future health maintenance, by clarifying the molecular mechanism leading to various diseases. In addition, basic and clinical researchers in the fields of structural biology, immunology, metabolism, and the nervous system, as well as researchers from different fields such as analytical chemistry and bioinformatics, will gather together in addition to the protein and glycoscience research fields in order to promote innovative and highly unique research and development by utilizing the strengths of each other's fields.

*“Proteostasis” means a series of processes that control the amount, quality, and localization of proteins in the homeostatic maintenance function of living organisms.

2. Targets

Focusing on the homeostasis of proteins inside and outside the cell (proteostasis), this research and development objective aims to clarify the mechanism of disease onset and create innovative medical technologies by analyzing the dynamics of degeneration, aggregation, decomposition, etc. from the cell to the individual level. In particular, the following three targets are to be achieved.
(1) Improved understanding of the environment surrounding proteins involved in proteostasis at the molecular level
(2) Elucidation of the mechanism of disease onset resulting from the disruption of proteostasis
(3) Development of seeds for therapeutic drugs and biomarkers targeting the mechanisms by which proteostasis disrupts

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Office for Basic Research Projects, Basic Research Promotion Division, Research Promotion Bureau