Cardiocyte apoptosis has been documented in many clinically important conditions including human and experimental heart failure. However, the intracellular pathways controlling cardiocyte cell death and the functional contribution of apoptosis to cardiac disease pathogenesis, have not been delineated. The goals of this proposal are to understand the role of PI 3-kinase signaling pathways in blocking cardiocyte apoptosis and the functional significance of cardiocyte apoptosis in an experimental model of heart failure. Insulin-like growth factor-I (IGF-I) has beneficial effects on both cardiocyte function and survival. IGF-I can both induce cardiac hypertrophy and block cardiocyte apoptosis. Binding of IGF-I to its receptor initiates a complex array of signaling events. In many systems, activation of phosphatidylinositol (PI) 3-kinase is critical to the ability of IGF-I to block apoptosis. In contrast, the Ras/MAP (mitogen-activated protein) kinase pathway has been associated with cardiac hypertrophy and malignant transformation. Recently, the serine- threonine kinase, Akt, has been identified as both necessary and sufficient for the ability of PI 3-kinase to block apoptosis in neurons. This proposal is based on three hypotheses: 1) that the signaling pathways responsible for the ability of IGF-I to induce hypertrophy and block apoptosis are distinct; 2) that activation of PI 3-kinase accounts for the beneficial effects of IGF-I on cardiocyte survival through Akt- mediated inhibition of caspase-dependent apoptosis, and 3) that apoptosis contributes significantly to the development of cardiac dysfunction in heart failure. To test these hypotheses, we will use adenoviral vectors to express wild-type and mutant forms of specific signaling molecules in cardiocytes in vitro and in vivo.
In Specific Aim 1, we will develop and characterize the necessary vectors.
In Specific Aim 2, we will examine the effects of these molecules on cardiocyte apoptosis, function, and hypertrophy in vitro.
In Specific Aim 3, we will study the role of the same pathways in cardiac apoptosis and function in a rat model of pressure overload-induced heart failure. Understanding the role of specific signaling pathways in cardiocyte apoptosis and developing approaches to local modulation of these pathways through somatic gene transfer, may provide novel therapeutic approaches for the management of many clinically important disorders.
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