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

平滑肌细胞脂肪酸氧化在肺动脉高压发病机制中的作用

• 批准号: 10622011
• 负责人: Michael Hyunjean Lee
• 金额: $ 3.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-17 至 2022-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10622011
• 关键词: Address; Affect; Animal Model; Area; Award; Biology; Blood Circulation; Blood Vessels; Cell Count; Cell Proliferation; Cells; Chronic; Clinical; Clinical Sciences; Colorado; Data; Dedications; Development; Disease; Endothelium; Environment; Exposure to; Fatty Acids; Glucose; Glycolysis; Home; Human; Hypoxia; Institutes; Institution; Knowledge; Laboratories; Left; Link; Literature; LoxP-flanked allele; Lung; MYH11 gene; Measures; Metabolic; Metabolism; Methods; Mitochondria; Morality; Mus; Oxygen; Palmitates; Pathogenesis; Patients; Physicians; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary artery structure; Rattus; Research; Research Methodology; Research Personnel; Research Project Grants; Research Training; Resources; Role; Science; Scientist; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Source; Specimen; Systolic Pressure; Tamoxifen; Testing; Therapeutic; Tissue Banks; Training; Translational Research; Up-Regulation; Vascular Smooth Muscle; Ventricular; Water; Work; aerobic glycolysis; base; cell type; experience; experimental study; fatty acid oxidation; human subject; hypoxia-induced pulmonary hypertension; inhibitor; mouse model; novel; oxidation; protective effect; pulmonary arterial hypertension; pulmonary vascular cells; pulmonary vascular disorder; pulmonary vascular remodeling; right ventricular remodeling; skills; statistics; therapeutic target

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.

项目摘要/摘要 拟议研究计划的中心重点是研究脂肪酸氧化的致病作用。 肺动脉高压时肺动脉平滑肌细胞的变化。而线粒体的变化 能量底物的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(即葡萄糖氧化与糖酵解)对 肺血管系统--以脂肪酸作为替代线粒体氧化底物的意义 很大程度上是未被开发的。此外，线粒体代谢变化与肺损伤的关系机制 高血压仍不为人所知。填补这些知识空白将使我们更深入地了解 肺动脉高压的发病机制，并介绍新的潜在治疗靶点。基于健壮性 初步数据，这位申请人建议调查平滑肌细胞脂肪酸氧化在 使用患者来源的人类细胞和新开发的小鼠模型发展肺动脉高压。 具体地说，他将对失败的肺捐赠者的肺动脉平滑肌细胞中的脂肪酸氧化进行量化 和肺动脉高压患者从肺动脉高压中获得突破 组织银行倡议，他还将评估脂肪酸氧化对平滑肌细胞的影响 增殖(目标1)。使用最近产生的SMMHC-CreERT2 x CPT1a绒毛小鼠品系，这位申请人 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 足以保护小鼠免受缺氧性肺动脉高压的影响(目标2)。预期的 这些实验的发现将重新确定平滑肌细胞脂肪酸的致病作用 氧化在肺动脉高压中的作用和产生新的假说侧重于阐明线粒体如何 信号转导会导致肺动脉高压。这些新的假设将构成申请者未来的基础 作为独立研究人员的研究资助，包括K08奖。申请人的研究环境 非常适合培养他成为一名独立的内科科学家。他将在一个实验室工作，与 在涉及人类标本和小鼠模型的肺血管研究方面有数十年的经验。 申请者将加强他的假设生成技能和他的实验的严密性 通过积极参加研究生级课程提供的研究方法和统计方法 科罗拉多州临床与翻译科学研究所。他还将与世界知名的 来自他所在机构内外的新陈代谢和肺血管疾病专家。 有了这些全面的研究培训资源和对科学的奉献精神，申请者将开始 在肺动脉高压的背景下发展线粒体生物学方面的独特专业知识。

项目成果

Pulmonary Arterial Hypertension and Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Novel Association?

肺动脉高压与胰腺导管内乳头状粘液性肿瘤：一种新的关联？

• DOI: 10.1016/j.chest.2021.06.078
• 发表时间: 2021
• 期刊: Chest
• 影响因子: 9.6
• 作者: Lee,MichaelH;Doran,Jennifer;Bang,TamiJ;Hohsfield,Robin;Hountras,Peter;Boddie,Genevieve;Wagh,MihirS;Badesch,David;Bull,ToddM
• 通讯作者: Bull,ToddM