This represents a competing renewal application to study gene transfer as a means to alter the function of transplanted hearts. Cardiac transplantation is limited by the limited supply of donor hearts and perioperative ventricular dysfunction. Ventricular dysfunction (including RV dysfunction due to recipient pulmonary hypertension) and allograft vasculopathy are major causes of cardiac transplant failure. Understanding signaling mechanisms may be important to improve graft function and survival. Signaling through G-protein coupled receptors (GPCR), especially BAR, is important for normal cardiac and vascular smooth muscle cell physiology. BAR signaling is often compromised in the transplanted human heart, and several agents implicated in allograft vasculopathy can signal through G proteins. Transgenic mice have been developed with altered BAR and G protein signaling, including mice in which BAR-kinase (BARK1) is overexpressed. Increased expression of a BARK1 inhibitor improves cardiac performance in heart failure and transplant models. The plans are to use viral-mediated gene transfer in rat and rabbit models and transgenic mice models to investigate mechanisms by which GPCR signaling affects graft function.
The Aims are (1) to characterize BAR signalling in brain dead rabbit hearts and to try to improve function with adenoviral delivery of BAR signalling/inhibitory molecules; (2) to characterize BAR signalling and elucidate molecular defects in murine cardiac grafts, to use transgenic BAR signaling mutants to determine effects on graft function, and to use a rabbit model of heterotopic cardiac transplantation to study the effects of acutely manipulating BAR signalling; (3) to use a pulmonary artery banding model in rabbits to produce RV stress, as a condition to test BAR signalling and as a means to improve posttransplant RV dysfunction; and (4) to study the role of G protein signalling in mediating vascular smooth muscle (VSM) cell proliferation, and to use a rat aortic allograft model to test strategies to limit VSM hyperplasia in transplantation.
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