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

项目摘要/摘要 肺动脉高压(PAH)是一种严重的进展性疾病，死亡率高达近 在5年内增长40%。肺动脉内皮细胞和平滑肌细胞(PAECs和PASMCs) 细胞内信号变化促进增殖、抗凋亡表型，从而导致 肺血管闭塞导致阻力增加。迫切需要发现 促进血管细胞重塑的机制。我们的长期目标是确定路径或分子 治疗干预的目标，以减轻以PAH为中心的血管异常 发展和进步。Sphk1和Sphingosine-1磷酸在肺和肺中的增加 PAH患者动脉平滑肌细胞和低氧肺损伤模型鼠肺组织中的血管平滑肌细胞 高血压(HPH)。线粒体(MT)功能障碍也通过改变对多个 MT过程，导致血管松弛受损和血管细胞增殖增加。然而， Sphk1/S1P信号轴在PAH发生发展中对mt功能的影响尚不清楚 明白了。我们的初步研究表明，S1P促进UPRmt的激活并调节mt 人PAECs和PASMCs的动力学。拟议研究的具体目标是确定 UPRmt信号介质在血管细胞功能中的作用。我们的中心假设是 Sphk1/S1P/S1PR信号轴调节UPRmt通路促进血管重塑，从而导致 多环芳烃的开发。这一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促进肺血管细胞增殖中的作用 增殖和低氧诱导肺高压(HPH)的发生。我们的工作假设是Sphk1/S1P/ S1PR信号轴调节线粒体功能，这是导致病理改变的主要原因 PASMCs和PAECs的增殖参与了PAH的发展。 目的：探讨UPRmt抑制对血管重塑和HPH发生的影响。我们的 工作假说是低氧诱导体内UPRmt的激活，导致血管重塑和 啊哈。 目的3：确定肺血管细胞和线粒体之间是否存在协调信号 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.