Project Summary This K08 proposal will expedite the principal investigator’s progress towards his goal of becoming an independent physician-scientist focused on increasing our understanding of pathogenic mechanisms of pulmonary hypertension (PH) and developing innovative therapies to improve outcomes. Candidate: Dr. Kel Vin Woo is a physician-scientist at Washington University School of Medicine (WUSM). He completed a fellowship in Pediatric Cardiology and is developing expertise at the intersection of Fibroblast Growth Factors (FGF) signaling and vascular biology under the mentorship of Dr. David Ornitz, a world authority on FGF biology. Under Dr. Ornitz’s mentorship, the PI investigated how endothelial FGF signaling modulates hypoxia-induced PH by mitigating endothelial-to-mesenchymal transition. He will leverage the skills gained during his fellowship to further analyze FGF signaling in vascular smooth muscle cells and use adenovirus- delivered endothelial FGF as a potential method of regulating vascular remodeling. Career Development Plan: Dr. Woo will pursue this line of research with primary mentorship from Dr. Ornitz and co-mentorship from Dr. Curiel (an expert in adenovirus vectorology). Additionally, a team of intramural and extramural advisors include experts in PH, and vascular and pulmonary biology, and all have considerable experience in nurturing independent investigators. WUSM provides a highly interactive environment with excellent facilities, resources and opportunities. This 5-year plan builds on the PI’s prior experience and further enriches his training, providing him with the tools needed for independence. It includes the following objectives: (1) Master techniques in advanced mouse hemodynamic phenotyping; (2) Become proficient with adenovirus engineering to improve PH outcomes using preclinical models of hypoxia-induced vascular remodeling; (3) Disseminate research findings in diverse venues and actively establish productive collaborations. Research Plan: The overall hypothesis of the proposal is that FGF signaling in lung endothelial and vascular smooth muscle cells protects against hypoxia-induced PH. Specific Aim 1 will investigate how smooth muscle cell FGF prevents pulmonary vascular remodeling. Aim 2 will interrogate how endothelial targeted adenovirus- delivered FGF reduces hypoxia-induced vascular remodeling and PH severity. Upon completion of the proposed research, Dr. Woo will be proficient in: (1) modulating intracellular pathways important for endothelial and smooth muscle cell remodeling; (2) analyzing newly developed conditional knockout mice to ascertain the hemodynamic effects on the lungs; and (3) developing approaches for gene delivery to lung endothelium as a potential therapy for pulmonary vascular disease. These acquired skills will be readily applicable to other forms pulmonary vascular disease and endothelial-smooth muscle interactions in vascular remodeling. Upon completion of the proposed traini...