This application for a Mentored clinical Scientist Development Award is designed to provide the principal investigator (P.I.), Dr. Lynell Johnson, with the research skills and expertise needed to develop into an independent researcher in the field of cardiopulmonary research. Experience gained through completion of the research described will provide the P.I. with the skills needed to investigate more fully the physiology and molecular mechanisms involved in regulation of pulmonary vasoreactivity. With this knowledge, the P.I. can go beyond clinical studies of pulmonary diseases to engage in complementary scientific research. The P.I. is currently enrolled in a doctoral program with the Department of Veterinary Biomedical Sciences. Faculty members in this department are devoted to the study of cardiovascular disease and the benefits of exercise training on the vascular function, thus providing an excellent support system for the research described. The research planned will investigate the role of nitric oxide (NO) in enhancement of endothelium-dependent vasodilation in the pulmonary circulation using a porcine model of exercise training. Nitric oxide is recognized as an important endothelium-derived regulator of vascular responses in health individuals, and defects in NO-mediated responses are suspected in a number of pathophysiologic states. The central hypothesis of this research is that exercise training results in sustained adaptations in the pulmonary circulation through enhanced endothelium-mediated control of pulmonary vascular reactivity. The research proposed will utilize five methodologies encompassing basic physiology, biochemistry, and molecular biology, to test three hypotheses: 1) Increased blood flow associated with chronic exercise training leads to increased NO synthase and improved endothelium- mediated vasorelaxation in pulmonary arteries to exercise trained pigs, 2) Increased NO synthase induced by exercise training allows maintenance of lower vascular resistance at any give perfusion pressure in exercise trained subjects and reduces hypoxic pulmonary vasoconstriction, and 3) Increased blood flow through the lung leads to increased mRNA for nitric oxide synthase, thus providing a mechanism for improvement in endothelium-dependent vasorelaxation. The long term goal of this research is to gain the expertise needed for the P.I. to become an established investigator in cardiopulmonary research and to pursue independent funding for comparative studies on endothelium-mediated alterations in pulmonary vascular control in health and disease.
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