The Role of Smooth Muscle Cell Fatty Acid Oxidation in the Pathogenesis of Pulmonary Hypertension

项目总结/摘要 拟议的研究计划的中心焦点是调查脂肪酸氧化的发病作用， 肺动脉平滑肌细胞在肺动脉高压中的作用虽然线粒体的改变 能量底物利用与肺动脉高压的发病机制有关， 研究主要集中在葡萄糖利用的影响（即，葡萄糖氧化与糖酵解） 肺血管，脂肪酸作为线粒体氧化底物的重要性 大部分未被探索。此外，线粒体代谢变化与肺动脉高压之间的联系机制， 高血压仍然未知。填补这些知识空白将有助于更深入地了解 肺动脉高压的发病机制，并引入新的潜在的治疗靶点。基于鲁棒 根据初步数据，本申请人提出研究平滑肌细胞脂肪酸氧化在 肺动脉高压的发展使用患者来源的人类细胞和新开发的小鼠模型。 具体来说，他将量化失败的肺供体的肺动脉平滑肌细胞中的脂肪酸氧化 和肺动脉高压突破中获得的肺动脉高压患者 他还将评估脂肪酸氧化对平滑肌细胞的影响 增殖（目的1）。使用最近生成的SMMHC-CreERT 2 x CPT 1a floxed小鼠系，本申请人 将选择性地阻断平滑肌细胞中的脂肪酸氧化，并测试这种代谢变化是否 足以保护小鼠免于发展缺氧诱导的肺动脉高压（目的2）。预期 这些实验的发现将重新确立平滑肌细胞脂肪酸的致病作用 氧化在肺动脉高压和产生新的假说，重点是阐明如何线粒体 信号传导导致肺动脉高压。这些新的假设将构成申请人未来的基础 作为独立研究人员获得研究赠款，包括K 08奖。申请人的研究环境 非常适合培养他成为一名独立的医学科学家。他将在实验室工作， 在涉及人类标本和小鼠模型的肺血管研究方面拥有数十年的经验。 申请人将加强他的假设生成技能和他的实验的严格性， 通过积极参加研究生水平的研究方法和统计学课程， 由科罗拉多临床和转化科学研究所。他还将与世界知名的 来自他所在机构内外的代谢和肺血管疾病专家。 有了这些研究培训的综合资源和他对科学的奉献精神，申请人将开始 在肺动脉高压的背景下发展线粒体生物学的独特专业知识。

Project Summary/Abstract 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.