G PROTEIN SIGNALING AND CARDIOMYOPATHY

University Of California San Francisco, San Francisco CA

Investigators

Linked publications & trials

Abstract

The goal of this proposal is to test the hypothesis that chronically increased GI signaling causes impaired contractile function of the myocardium. This hypothesis will be tested by combining a transgenic mouse model that has hyperactive Gi signaling, with the use of sophisticated measurements of physiological function of mouse myocardium. Myofilament force and shortening velocity will be measured while measuring and controlling sarcomere length. Furthermore, accurate calibrated measures of intracellular calcium transients will be made using fluorescent calcium probes. This combination of transgenic technology and detailed measures of physiological function at the level of the cardiac sarcomere will be a powerful approach to investigate cardiac disease. Gi signaling will be controlled in mouse hearts using novel transgenic mice that express Gi- coupled G protein coupled receptors (GPCR) and which develop dilated cardiomyopathy. The hypotheses of this proposal will be tested in 3 specific aims: 1. Determine the effects of Gi coupled GPCR expression on the isometric and isotonic mechanical properties of mouse cardiac muscle trips (RV trabeculae). To verify that the effects are due to increased Gi signaling, control experiments will use pertussis toxin to inhibit Gi signaling. 2. Determine if impaired myocardial function with increased Gi signaling is caused by reduced contractile protein function or by impaired Ca2+ handling. 3. Determine if terminating expression of the Gi coupled GPCR results in recovery of contractile function. This specific aim addresses whether strategies that restore the normal balance of Gi signaling in the heart can ameliorate cardiac pathology. The long term goal of this proposal is to understand the role of Gi signaling in causing impaired physiological function which may help identify new therapeutic targets to improve cardiac function during disease.