CARDIAC GENE THERAPY

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

The proposed research seeks to delineate the mechanisms underlying the progressive development of dilated cardiomyopathy and failure following myocardial infarction. We also will examine resetting of the calcium set point for contractility as a potential strategy to blunt hypertrophic drive resulting from pressure overload. In doing so, we will evaluate AAV-gene transfer approaches for the treatment of heart failure. First we will evaluate the hypothesis that an apoptotic component drives the dilated cardiomyopathy that follows focal infarction. The stimulus arises from stretch that is imposed on the border zone cells following rigidification of the infarct zone. Continuous inhibition of cell death is necessary to prevent the development of dilated failure. The ability of overexpression of the anti-apoptosis factors Bcl-2, hepatocyte growth factor (HGF) and dominant negative phospholamban to impact the development of dilated cardiomyopathy will be tested. In addition, we will analyze these transgenes and a novel transgene (arginine kinase) in a mouse model of atherosclerosis, in which there is global ischemia and focal infarction. Lastly, we will alter the calcium sensitivity of the cardiac troponin complex in an attempt to blunt pressure overload hypertrophy and the subsequent progression to failure.