Dysfunction of the diseased heart is the main cause of death in this country. For young adults, a leading cause of sudden death is hypertrophic cardiomyopathy (HCM), in which a link has been established between cardiac dysfunction and missense mutations of several key myofilament genes expressed in the cardiac sarcomere. Genetic modification of cardiac muscle holds promise as one mechanism to correct inherited cardiac disease. The primary goal of this proposal is to modify heart contractile performance in vivo using recombinant adenovirus-mediated myofilament gene transfer. Adenovirus vectors for the delivery and expression of normal sarcomeric genes in the myocardium represents a potentially efficient means for the correction of disease-related cardiac contractile dysfunction. Important and unresolved questions that will be addressed by this proposal relate to the efficacy of myofilament gene transfer for modification of heart performance. A primary concern centers on the stability of gene expression in the myocardium. There are, however, no reports on the efficiency or stability of myofilament gene transfer in the heart in vivo. In addition, the influence of aging on the efficiency and stability of myofilament gene transfer and expression has not been established. Finally, and most critically, the effects of myofilament gene transfer on cardiac sarcomere structure and function in vivo are not known, and these effects will be evaluated for the first time in this proposal. In addition, issues regarding the efficiency and stability of myofilament gene expression will be assessed in neonatal, adult and aged animals using first and second generation, """"""""gutted"""""""" adenoviral vectors. The working hypothesis of this application is that gene delivery into the heart in vivo by gutted adenoviral vectors will prolong the stability and improve the efficiency of myofilament gene expression in cardiac myocytes.
The Specific Aims and hypotheses are 1. Gene transfer into the heart in vivo by gutted adenoviral vectors will a) increased the stability, and b) improve the efficiency of myofilament gene expression in cardiac myocytes. 2. Consequent to myofilament gene transfer into the heart in vivo, the efficiency had stability of gene expression will be reduced in old animals as compared with neonatal or adult animals. 3. Myofilament gene transfer into the heart in vivo will result in a) normal incorporation of the expressed contractile protein into the sarcomere, b) retention of the normal stoichiometry of the multimeric cardiac contractile assembly, and c) modified contractile performance of the cardiac pump.

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National Institute on Aging (NIA)
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University of Michigan Ann Arbor
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