Knock-in mouse model of hypertrophic cardiomyopathy caused by troponin T mutation

2014 Fiscal Year Final Research Report

• Project/Area Number: 24790791
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Circulatory organs internal medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: DU Cheng-Kun 独立行政法人国立循環器病研究センター, 研究所, 研究員 (90590646)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 肥大型心筋症 / ノックインマウス / 突然死 / 心筋トロポニンT / 遺伝子変異 / カルシウム感受性

Outline of Final Research Achievements

We created knock-in mice with a missense mutation S179F in cardiac troponin T (cTnT), which had been found to be associated with human hypertrophic cardiomyopathy (HCM). Membrane-permeabilized cardiac muscle fibers from these mice showed significantly higher Ca2+ sensitivity in force generation than those from wild-type mice. The knock-in mice suffered from sudden death frequ ently, and histological examination of cardiac sections showed significant displacement fibrosis, myocardial hypertrophy, and myocyte disarray. Echocardiography showed that left ventricular (LV) end-diastolic dimension was significantly decreased with no changes in ejection fraction. In vivo cardiac catheter measurements showed a significant increase in LVdP/dtmin with no changes in LVdP/dtmax. These results indicate that the knock-in mouse with S179F mutation in cTnT is a useful mouse model of HCM closely capitulating the clinical phenotypes of human patients.

Free Research Field

循環器内科学