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Abstract

Grant Number:	5P01HL059407-100002
Project Title:	CARDIAC GENE THERAPY

PI Information:	Name	Email	Title
	SWEENEY, HUGH LEE.	lsweeney@mail.med.upenn.edu	PROFESSOR AND CHAIRMAN

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.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
gene therapy, heart failure, idiopathic dilated cardiomyopathy, nonhuman therapy evaluation, pathologic process
BCL2 gene /protein, adeno associated virus group, apoptosis, calcium flux, cardiac myocyte, cardiovascular disorder therapy, cytoprotection, hepatocyte growth factor, myocardial infarction, transfection /expression vector, tropomyosin, troponin
biotechnology, genetically modified animal, laboratory mouse, laboratory rabbit

Institution:	UNIVERSITY OF PENNSYLVANIA
	3451 Walnut Street
	PHILADELPHIA, PA 19104
Fiscal Year:	2008
Department:
Project Start:
Project End:
ICD:	NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
IRG:	HLBP

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