The central purpose of this Mentored Clinical Scientist Development Award is to prepare the applicant for a career as an independent investigator in anesthesiology. 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 sarcoplasmic reticulum in human and animal models of cardiomyopathy. The applicant proposes to acquire additional skills in molecular biology and somatic gene transfer in the context of a project that builds upon his previous experience in Ca 2+ homeostasis in heart failure in the laboratory of Dr. Roger Hajar at the Cardiovascular Research Center. Heart failure is a major cause of morbidity and mortality in the United States. In addition, it is a major determinant of intra-operative morbidity and mortality. Apoptosis is an important contributing factor in the pathogenesis of heart failure. Genes of the bcI-2 family are critically involved in the apoptotic process. The anti-apoptotic protein bcl-2 has recently been shown to alter Ca++ homeostasis by interacting with the sarcoplasmic reticulum in several non-contracting cells. Herein we propose the following hypotheses. 1) overexpression of bcl-2 will alter sarcoplasmic reticulum function in cardiomyocytes and thereby alter Ca++ homeostasis in these cells. 2) These changes in Ca 2++ homeostasis will alter cardiac function. 3) Overexpression of bcl-2 will improve survival, cardiac performance and Ca++ handling in the failing heart. To test these hypotheses the applicant plans 1) to study the effects of bcI-2 in isolated ventricular myocytes. 2) to characterize the effects of adenoviral gene transfer of bcI-2 to rat myocardium in vivo. 3) to study the effects of bcl-2 overexpression on myocardial fuction in rats with pressure overload hypertrophy in transition to failure. The ability to modify apoptosis and contractile properties in heart failure would represent an important step towards developing new therapeutic approaches for heart failure.
| Zhu, Xinsheng; Bagchi, Aranya; Zhao, Huailong et al. (2007) Toll-like receptor 2 activation by bacterial peptidoglycan-associated lipoprotein activates cardiomyocyte inflammation and contractile dysfunction. Crit Care Med 35:886-92 |
| Zhu, Xinsheng; Altschafl, Beth A; Hajjar, Roger J et al. (2005) Altered Ca2+ sparks and gating properties of ryanodine receptors in aging cardiomyocytes. Cell Calcium 37:583-91 |
| Zhu, Xinsheng; Bernecker, Oliver Y; Manohar, Naveen S et al. (2005) Increased leakage of sarcoplasmic reticulum Ca2+ contributes to abnormal myocyte Ca2+ handling and shortening in sepsis. Crit Care Med 33:598-604 |
