This proposal describes a 5-year training program for the development of an academic career in translational cardiovascular research. The candidate, having completed a clinical fellowship in Pediatric Critical Care Medicine, and a research fellowship at the Cardiovascular Research Institute (CVRI) at the University of California San Francisco (UCSF), is now poised to fully develop the scientific skill-set necessary to sustain an independent research program, utilizing the renowned, multidisciplinary environment offered by the CVRI and UCSF. The training program is designed to enable the candidate to apply integrated anatomic, physiologic, biochemical, cellular, and molecular investigations to addressing mechanisms of pulmonary vascular disease associated with congenital heart defects. The sponsor, Jeffrey R. Fineman, M.D., a Professor at UCSF and an internationally recognized expert in pulmonary vascular disease, has a strong history of successful mentorship. In addition, an advisory committee of distinguished medical scientists will provide additional scientific support and career guidance. Practical training in experimental techniques, design, and analysis Is combined with complementary didactic course-work. The proposed research plan seeks to elucidate the mechanisms underlying the development of pulmonary vascular disease secondary to increased pulmonary blood flow that is associated with several congenital heart defects. Previous work from Dr. Fineman's laboratory demonstrates that aberrant nitric oxide (NO) and endothelin-1 (ET-1) signaling contribute to this pathology. The candidate has subsequently generated preliminary data, which suggest a central role for PPARY in these interactions. Utilizing a unique clinically relevant ovine model of a congenital heart defect with increased pulmonary blood flow (created in utero by an aorto-pulmonary graft), and integrated biochemical, molecular, and cellular experiments, the proposal seeks to accomplish the following aims: (1) To determine alterations in endogenous PPARy expression under conditions of increased pulmonary blood flow, and the mechanisms and functional consequences of these alterations;and (2) To determine the physiologic, biochemical, cellular, and molecular alterations induced by PPARy agonist therapy under conditions of increased pulmonary blood flow. A role for PPARy in this pathology is novel. A better understanding of these interactions may have important implications for pulmonary as well as systemic vascular disorders. Relevance: Infants and children afflicted with congenital heart defects with increased pulmonary blood flow, suffer morbidity and mortality from the development of pulmonary vascular disease. Understanding the controlling mechanisms of this pathology might lead to novel and effective prevention and treatment strategies that will improve the survival and quality of life of this vulnerable population.
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