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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要拟议研究计划的中心重点是通过以下方式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线粒体发生改变。能量底物利用与肺动脉高压的发病机制有关，既往研究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，脂肪酸作为替代线粒体氧化底物的重要性此外，线粒体代谢变化与肺功能之间的联系机制在很大程度上尚未被探索。填补这些知识空白将有助于更深入地了解高血压。肺动脉高压的发病机制并引入基于稳健的新的潜在治疗靶点。初步数据，本申请人提议研究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进行肺动脉高压的发展。具体来说，他将量化失败肺捐赠者肺动脉平滑肌细胞中的脂肪酸氧化以及从肺动脉高压突破中获得的肺动脉高压患者倡议组织库，他还将评估脂肪酸氧化对平滑肌细胞的影响该申请人使用最近生成的 SMMHC-CreERT2 x CPT1a floxed 小鼠系。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是足以保护小鼠免受缺氧引起的肺动脉高压（目标 2）。这些实验的结果将新确定平滑肌细胞脂肪酸的致病作用肺动脉高压中的氧化并产生新的假设，重点是阐明线粒体如何这些新的假设将构成申请人未来的基础。作为独立研究员的研究补助金，包括申请人的研究环境。非常适合训练他成为一名独立的医师科学家，他将在实验室工作。在涉及人体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实验的严格性通过积极参加有关研究方法和统计学的研究生课程他还将与世界知名的机构合作。来自其所在机构内外的代谢和肺血管疾病专家。凭借这些全面的研究培训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。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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：
发表时间：
2021-12
期刊：
影响因子：
9.6
作者：
Lee, Michael H;Doran, Jennifer;Bang, Tami J;Hohsfield, Robin;Hountras, Peter;Boddie, Genevieve;Wagh, Mihir S;Badesch, David;Bull, Todd M
通讯作者：
Bull, Todd M