The main goal of this proposal is the exposure of our undergraduate and graduate students to meritorious research on alcohol-induced heart failure. Alcoholic cardiomyopathy is characterized by a number of abnormalities at the cellular level in the various steps of excitation-contraction coupling. Two key abnormalities in experimental alcoholic cardiomyopathy are 1) a defect in sarcoplasmic reticulum (SR) function which is associated with abnormal intracellular Ca2+ handling and 2) reduced myocardial phosphatidylinositol (PI3)- kinase activity and elevated free-radicals expression (90). Deficient SR Ca2+ uptake during relaxation has been identified in alcoholic hearts and has been associated with a decrease in the expression and activity of SR Ca2+-ATPase (SERCA2a) along with changes in the expression of phospholamban. Furthermore, a decrease in PI3 kinase activity leading to a decrease in Akt activation and subsequently an increase in free-radicals expression leads to heart failure (69). The overall goal of the current proposal is to delineate the links between PI3K signaling and the preservation of cardiac function in the context of alcohol intake. It is our hypothesis that during low alcohol intake, PI3K signaling reduces free-radical stress and preserves SERCA2a function;whereas high alcohol intake disrupts the PI3K signaling and remove its protective role against free-radical stress and SERCA2a function. The objectives of this proposal are to understand the roles of specific downstream signaling pathways in shifting the beneficial cardioprotective effects of low alcohol into a detrimental alcoholic cardiomyopathy and heart failure with chronic exposure. Animal models of moderate and high alcohol chronic exposure will be utilized in addition to primary cultures of adult rat ventricular myocytes for corroborative in vivo and in vitro studies. This proposal is based on three hypotheses: 1) that the signaling pathways controlling cardiocyte survival are decreased in alcoholic cardiomyopathy;2) that activation of PI-3K improves survival in cardiocytes through Akt;3) that pro-apoptotic signaling pathways contribute significantly to the development of cardiac dysfunction in alcohol induced heart failure. To test these hypotheses, we will use recombinant associated adenoviral vectors to overexpress wild-type and mutant signaling molecules in cardiocytes in vitro and in vivo. The effects of these constructs on cardiocyte function and survival will be examined in both in vitro and in vivo models.

PUBLIC HEALTH RELEVANCE: This proposal engages undergraduate and graduate students in meritorious research on the role of intracellular molecules, known to enhance cellular survival, in the beneficial effects seen with low alcohol intake. We hypothesize that by reducing cellular oxidative stress, this series of molecules, called PI3K/Akt, maintains calcium homeostasis to improve cardiac function. On the contrary, excessive alcohol intake induces cellular stress and cardiac dysfunction by dampening the role of these survival molecules. Using targeted somatic gene transfer therapy we propose to monitor these survival molecules to alleviate the impending alcohol-induced cardiac dysfunction.

R15AA019816

2011-09-20

2015-08-31