Analysis and application of GPCR/G protein diseases

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K09034
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: Iiri Taroh 聖マリアンナ医科大学, 医学部, 教授 (90313022)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: GPCR / G蛋白質 / バイアスアゴニズム / ニトロシル化 / 疾患解析制御

Outline of Final Research Achievements

GPCR diseases and G protein diseases tell us how GPCRs/G proteins work and hint at how to develop small molecules that work as potential therapeutics. In this study, 1) we have analyzed GPCR diseases (diseases caused by either GPCR autoantibodies or their mutations), clarified how GPCRs/G proteins work, and developed potential therapeutics using small molecules. 2) We have also designed small molecules that nitrosylate and inhibit GRK2, a GPCR kinase that plays important role in GPCR desensitization, analyzed their structure-function relationship, and identified and analyzed small molecules accelerating lipolysis. 3) We have also analyzed how GPCRs and their molecular defects work based on accumulating evidence on these diseases and structural analyses.

Free Research Field

内分泌学、細胞分子薬理学、内科学、GPCRシグナル制御と疾患

Academic Significance and Societal Importance of the Research Achievements

GPCRやGタンパク質の分子異常を原因とする疾患の解析は、疾患メカニズムとともにこれらシグナル分子群の生理的作用機構そのものの解明に大いに貢献してきた。これらの蓄積されたデータと近年進歩が著しい構造解析データを統合することで、疾患における分子異常と正常機能の詳細解明が可能となり、潜在的な治療法となるシグナル異常を正す小分子化合物の開発へと展開してゆくことが期待される。