The central focus of the proposed research plan is to investigate the pathogenetic role of fatty acid oxidation by the pulmonary arterial smooth muscle cells in pulmonary hypertension. While alterations in mitochondrial energy substrate utilization have been implicated in the pathogenesis of pulmonary hypertension, previous studies have mostly focused on the impact of glucose utilization (i.e., glucose oxidation vs. glycolysis) on the pulmonary vasculature, with the significance of fatty acid as an alternative mitochondrial oxidative substrate largely left unexplored. Moreover, the mechanism linking mitochondrial metabolic changes and pulmonary hypertension remains unknown. Filling these knowledge gaps will allow a deeper understanding of the pathogenesis of pulmonary hypertension and introduce novel potential therapeutic targets. Based on robust preliminary data, this applicant proposes to investigate the role of smooth muscle cell fatty acid oxidation in pulmonary hypertension development using patient-derived human cells and a newly developed mouse model. Specifically, he will quantify fatty acid oxidation in pulmonary arterial smooth muscle cells of failed lung donors and patients with pulmonary arterial hypertension obtained from the Pulmonary Hypertension Breakthrough Initiative tissue bank, and he will also assess the impact of fatty acid oxidation on smooth muscle cell proliferation (Aim 1). Using the recently generated SMMHC-CreERT2 x CPT1a floxed mouse line, this applicant will selectively block fatty acid oxidation in the smooth muscle cells and test whether this metabolic change is sufficient to protect the mice from developing hypoxia-induced pulmonary hypertension (Aim 2). Anticipated findings of these experiments will newly establish the pathogenetic role of smooth muscle cell fatty acid oxidation in pulmonary hypertension and generate novel hypotheses focused on elucidating how mitochondrial signaling results in pulmonary hypertension. These new hypotheses will form the basis of the applicant?s future research grants as an independent researcher, including the K08 award. The applicant?s research environment is ideally-suited to train him to become an independent physician-scientist. He will work in a laboratory with decades of experience in pulmonary vascular research involving both human specimens and murine models. The applicant will strengthen his hypothesis-generating skills and the stringency of his experimental approaches by actively participating in graduate level courses on research methodology and statistics offered by the Colorado Clinical and Translational Sciences Institute. He will also collaborate with world-renowned experts in metabolism and pulmonary vascular diseases from both within and outside of his home institution. With these comprehensive resources for research training and his dedication to science, the applicant will start to develop a unique expertise in mitochondrial biology in the context of pulmonary hypertension.
Pulmonary arterial hypertension is currently an incurable disease with a high associated morality, and the difficulty in treating patients affected by pulmonary arterial hypertension reflects the need for a deeper understanding of its pathogenesis. While mitochondrial fatty acid oxidation appears to significantly contribute to pulmonary hypertension development, this promising area of research largely remains unexplored. Identifying the type of pulmonary vascular cells responsible for fatty acid oxidation-induced pathogenesis of pulmonary hypertension and uncovering the underlying mechanism will enhance our understanding of the disease and introduce new potential therapeutic targets.
