Establishment of analysis method of ryanodine receptor arrhythmogenic mutations and its application to therapeutic drug screening

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K08243
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Juntendo University
• Principal Investigator: Kurebayashi Nagomi 順天堂大学, 医学部, 先任准教授 (50133335)
• Research Collaborator: MURAYAMA takashi ; YAMASHITA fumiyoshi
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: リアノジン受容体 / 不整脈 / 心臓 / カルシウム / 抗不整脈薬

Outline of Final Research Achievements

In this project, we aimed to understand the mutant RyR2-related arrhythmogenic mechanism and to establish a screening procedure for RyR2 inhibitors as anti-arrhythmic drugs. First, functional evaluation of RyR2 mutations were carried out using HEK cell expression system and a cardiomyocyte cell line. We found gain-of-function type and loss-of-function type of arrhythmogenic mutations. In the former, our functional analysis has proved to be very useful for predicting the severity of diseases caused by the mutations. Next, we developed a screening system for specific RyR2 inhibitors utilizing the ER Ca2+ monitoring, which was found to be an accurate indicator of RyR2 activity.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

我々が確立した機能解析系は疾患の重症度や治療方針の判断に有用である。不整脈治療薬に関してRyR2阻害薬が本当に抗不整脈作用を持つか未だ証明されていないため、新規のRyR2特異的な化合物の発見は不整脈の成り立ちを研究する上で学術的にも有用な発見である。またRyR2変異による不整脈疾患には現存の治療薬が効かない事が多いため、本研究により新分野の良い薬が見つかれば、不整脈を有する患者さんのQOL向上に役立つと考えられる。