Identification of Novel Molecular Targets and Drug Development by Genomic and Multilayer-Omics Analysis of Hereditary Cardiomyopathies

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03652
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Osaka University
• Principal Investigator: Asano Yoshihiro 大阪大学, 医学系研究科, 特任准教授(常勤) (60527670)
• Co-Investigator(Kenkyū-buntansha): 宮下 洋平 大阪大学, 医学系研究科, 助教 (60816312) ; 木岡 秀隆 大阪大学, 医学系研究科, 助教 (70642099) ; 塚本 蔵 大阪大学, 生命機能研究科, 准教授 (80589151)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 心筋症 / ゲノムデータベース構築 / オミックス研究 / 創薬治療法開発

Outline of Final Research Achievements

For drug discovery research and development related to hereditary cardiomyopathy and heart failure, we have identified the cause of the disease, searched for novel molecular targets, and established a research platform for the creation of cardiomyopathy drugs based on a bioactivity evaluation system. In addition to developing an integrated database of clinical and genomic variant information, we identified that homozygous truncating pathogenic variants in the gene encoding Bcl-2 associated athanogene (BAG) co-chaperone 5 (BAG5) among five patients with inherited dilated cardiomyopathy. BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), activating HSC70-mediated protein folding. Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an AAV-BAG5 gene could fully ameliorate these DCM phenotypes.

Free Research Field

循環器内科学、分子心臓病学

Academic Significance and Societal Importance of the Research Achievements

心筋収縮機構および恒常性に関与する新規遺伝子の同定を行うため、次世代ゲノム解析技術（全エクソーム解析、全ゲノム解析、構造解析、横断オミックス解析）を応用し、疾患バリアントの同定を行い、新規心筋症原因遺伝子を同定した。結果をもとに新規創薬標的の分子探索を実施し、心臓特異的な疾患原因分子の病態機序に立脚した効率的な研究基盤を構築し、大規模計算リソースを用いた情報解析を実施した。その結果、疾患ゲノムバリアントデータベースを構築した。その他にも機能未知の心筋症分子探索から疾患機序を同定し、その機能評価を行い、治療標的として導出した。