Regulation of UPRmt activation in the development of pulmonary vascular remodeling in PAH

UPRmt 激活在 PAH 肺血管重塑发展中的调节

• 批准号: 10508601
• 负责人: Angelia Denise Lockett
• 金额: $ 11.22万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10508601
• 关键词: Apoptosis; Blood Vessels; Caenorhabditis elegans; Cell Hypoxia; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Development; Endothelial Cells; Endothelium; Goals; Human; Hypoxia; Impairment; Intervention; Knowledge; Laboratories; Lead; Longevity; Lung; Lung diseases; Mediating; Mediator of activation protein; Mitochondria; Molecular; Outer Mitochondrial Membrane; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Phosphorylation; Phosphotransferases; Process; Prognosis; Progressive Disease; Proteins; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Quality of life; Regulation; Research; Research Personnel; Resistance; Respiration; Rodent; Rodent Model; Role; SPHK1 enzyme; Signal Transduction; Smooth Muscle Myocytes; Sphingolipids; Sphingosine; Testing; Therapeutic Intervention; Training Programs; Vascular remodeling; Vascular resistance; Vasodilation; Work; cancer cell; career; cell motility; improved; in vivo; mitochondrial dysfunction; mortality; new therapeutic target; novel; pulmonary arterial hypertension; pulmonary artery endothelial cell; pulmonary vascular cell proliferation; pulmonary vascular cells; pulmonary vascular remodeling; response; right ventricular failure; skills; sphingosine 1-phosphate; targeted treatment; tenure track; vascular abnormality

Project Summary/Abstract Pulmonary Arterial Hypertension (PAH) is a severe and progressive disease with a high mortality rate of nearly 40% over 5 years. Pulmonary artery endothelial and smooth muscle cells (PAECs and PASMCs) undergo intracellular signaling changes that promote a proliferative, apoptosis resistant phenotype that causes occlusion of the pulmonary vasculature leading to increased resistance. There is a critical need to uncover the mechanisms that promote vascular cell remodeling. Our long-term goal is to identify pathways or molecules to target for therapeutic intervention in order to alleviate the vascular abnormalities that are central to PAH development and progression. Sphk1 and sphingosine-1 phosphate are increased in the lungs and pulmonary artery smooth muscle cells of PAH patients and in the lungs of rodent models of hypoxia mediated pulmonary hypertension (HPH). Mitochondrial (mt) dysfunction also contributes to PAH via altered regulation of multiple mt processes, which leads to impaired vasorelaxation and increased vascular cell proliferation. However, the effect of the Sphk1/S1P signaling axis on mt function in the initiation or progression of PAH is not well understood. Our preliminary studies demonstrate that S1P promotes activation of the UPRmt and regulates mt dynamics in human PAECs and PASMCs. The specific objective of the proposed study is to determine the role of UPRmt signaling mediators on vascular cell function. Our central hypothesis is that activation of the Sphk1/S1P/S1PR signaling axis modulates the UPRmt pathway to promote vascular remodeling which leads to PAH development. This hypothesis will be tested by investigating the following specific aims: AIM 1: To investigate the role of the UPRmt in S1PRs/S1P/Sphk1 promotion of pulmonary vascular cell proliferation and hypoxia induced PH (HPH) development. Our working hypothesis is that the Sphk1/S1P/ S1PR signaling axis modulates mitochondrial function, which is a central cause underlying the pathological proliferation of PASMCs and PAECs to mediate PAH development. AIM 2: To determine the effects of UPRmt inhibition on vascular remodeling and HPH development. Our working hypothesis is that hypoxia induces activation of UPRmt in vivo resulting in vascular remodeling and PAH. AIM 3: Determine if coordinated signaling occurs between pulmonary vascular cells and mitochondrial processes to regulate vascular remodeling and HPH. Our working hypothesis is that coordinated signaling among the UPRmt, mitochondrial fission and mitochondrial respiration promote vascular remodeling.

项目概要/摘要 肺动脉高压（PAH）是一种严重的进行性疾病，死亡率高达近 5年内增长40%。肺动脉内皮细胞和平滑肌细胞（PAEC 和 PASMC）经历 细胞内信号传导的变化促进增殖、凋亡抗性表型，从而导致 肺血管闭塞导致阻力增加。迫切需要揭露 促进血管细胞重塑的机制。我们的长期目标是确定途径或分子 治疗干预的目标，以减轻 PAH 的核心血管异常 发展和进步。 Sphk1 和 sphingosine-1 磷酸盐在肺和肺中增加 PAH 患者的动脉平滑肌细胞和缺氧介导的肺啮齿动物模型的肺部 高血压（HPH）。线粒体 (mt) 功能障碍也通过改变多种机制的调节而导致 PAH mt 过程，导致血管舒张受损和血管细胞增殖增加。然而， Sphk1/S1P信号轴对PAH发生或进展中mt功能的影响尚不明确 明白了。我们的初步研究表明S1P促进UPRmt的激活并调节mt 人类 PAEC 和 PASMC 的动态。拟议研究的具体目标是确定 UPRmt 信号传导介质对血管细胞功能的作用。我们的中心假设是激活 Sphk1/S1P/S1PR信号轴调节UPRmt通路促进血管重塑，从而导致 多环芳烃的发展。该假设将通过调查以下具体目标来检验： 目的1：探讨UPRmt在S1PRs/S1P/Sphk1促进肺血管细胞中的作用 增殖和缺氧诱导 PH (HPH) 发展。我们的工作假设是 Sphk1/S1P/ S1PR信号轴调节线粒体功能，这是病理性的核心原因 PASMCs 和 PAECs 的增殖介导 PAH 的发展。 目标 2：确定 UPRmt 抑制对血管重塑和 HPH 发展的影响。我们的 工作假设是缺氧诱导体内 UPRmt 激活，导致血管重塑和 多环芳烃。 目标 3：确定肺血管细胞和线粒体之间是否存在协调信号传导 调节血管重塑和 HPH 的过程。我们的工作假设是协调信号 在 UPRmt 中，线粒体裂变和线粒体呼吸促进血管重塑。