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

项目概要/摘要 肺动脉高压（PAH）是一种严重的进行性疾病， 40%以上5年。肺动脉内皮细胞和平滑肌细胞（PAECs和PASMCs）经历 细胞内信号传导的变化，促进增殖，抗凋亡表型， 肺血管的阻塞导致阻力增加。迫切需要揭示 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，以缓解PAH的核心血管异常 发展和进步。SPHK 1和鞘氨醇-1磷酸在肺和肺动脉中增加， PAH患者的动脉平滑肌细胞和缺氧介导的肺损伤的啮齿动物模型的肺中的动脉平滑肌细胞 高血压（HPH）。线粒体（mt）功能障碍也可通过改变多种 MT过程，这导致血管舒张受损和血管细胞增殖增加。但 Sphk 1/S1 P信号轴在肺动脉高压的发生和发展中对mt功能的影响不明显 明白我们的初步研究表明，S1 P促进UPRmt的激活，并调节mt 在人PAEC和PASMC中的动力学。拟议研究的具体目标是确定 UPRmt信号介质对血管细胞功能的作用。我们的中心假设是， Sphk 1/S1 P/S1 PR信号轴调节UPRmt通路促进血管重构，导致 PAH发展。将通过调查以下具体目标来检验这一假设： 目的1：探讨UPRmt在肺血管细胞S1 PRs/S1 P/Sphk 1促增殖中的作用 增殖和缺氧诱导PH（HPH）的发展。我们的工作假设是Sphk 1/S1 P/ S1 PR信号轴调节线粒体功能，这是病理性线粒体损伤的核心原因。 PASMCs和PAECs的增殖介导PAH的发展。 目的2：探讨UPRmt抑制剂对血管重构和HPH发生的影响.我们 工作假设是缺氧诱导体内UPRmt活化，导致血管重塑， 呸。 目的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，线粒体分裂和线粒体呼吸促进血管重塑。

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.