The purpose of this Mentored Clinical Scientist Development Award is to prepare the applicant for a career as an independent investigator in cardiology. The applicant has developed a great interest in the cellular dysfunction observed in heart failure and has closely examined the role of abnormal calcium cycling in relation to the myofilaments and the sarcoplasmic reticulum in human and models of cardiomyopathy in the laboratory. The applicant proposes to build on his previous experience in cellular physiology of heart failure by examining the role of the sarcoplasmic reticulum ATPase in the development of heart failure using adenoviral gene transfer as a tool. Dr. Anthony Rosenzweig's laboratory in the Cardiovascular Research Center will provide the applicant with a rich intellectual environment to acquire a rigorous foundation in molecular biology and in adenoviral gene transfer. Heart failure is characterized by a number of abnormalities at the cellular level. One of the key abnormalities in both human and experimental heart failure is a defect in sarcoplasmic reticulum (SR) function which is associated with abnormal intracellular calcium handling. Deficient SR Ca2+ uptake during relaxation has been identified in failing hearts from both humans and animal models and has been associated with a decrease in the expression level of mRNAs encoding for SR Ca2+-ATPase. Recently, adenovirus vectors have been shown to be efficient in transferring exogenous genes into myocardial cells. Using replication-deficient recombinant adenovirus, the applicant plans to introduce the cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) gene directly into rats with pressure-overload induced heart failure. These rats are known to have a decrease in SERCA2a expression. The applicant will validate the use of adenoviral gene transfer in the rat model of heart failure and will test the hypotheses that diminished amounts of SERCA2a is important in the development of heart failure and that increasing the expression of SERCA2a will restore contractility and normalize intracellular calcium cycling in this model of heart failure.
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