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

基本信息

批准号：
10674631
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
项目类别：
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/10674631
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 Inhibition of Apoptosis Intervention Knowledge Laboratories Longevity Lung Lung diseases Mediating Mediator Mitochondria Molecular Outer Mitochondrial Membrane Pathogenesis Pathologic Pathway interactions Patients Pharmacologic Substance Phenotype Phosphorylation Phosphotransferases Process Prognosis Progressive Disease Proliferating 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

项目摘要

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.

项目摘要/摘要肺动脉高压（PAH）是一种严重且进行性疾病，高死亡率几乎在5年内40％。肺动脉内皮和平滑肌细胞（PAEC和PASMC）经历细胞内信号传导变化，促进了引起的增生性，凋亡的抗凋亡表型肺脉管系统的阻塞导致耐药性增加。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途径或分子治疗干预措施的靶标，以减轻PAH核心的血管异常发展和发展。 SPHK1和链球菌1磷酸盐在肺和肺中增加 PAH患者的动脉平滑肌细胞以及缺氧介导的肺啮齿动物模型的肺高血压（HPH）。线粒体（MT）功能障碍也通过改变多个的调节而导致PAH MT过程，导致血管延缓受损并增加血管细胞增殖。但是， SPHK1/S1P信号轴对PAH的启动或进展中MT功能的影响不好理解。我们的初步研究表明，S1P促进了UPRMT的激活并调节MT 人类PAEC和PASMC中的动力学。拟议研究的具体目标是确定 UPRMT信号介体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途径以促进血管重塑，这导致 PAH开发。该假设将通过研究以下特定目的来检验：目标1：研究UPRMT在S1PRS/S1P/SPHK1促进肺血管细胞中的作用增殖和缺氧诱导的pH（HPH）发育。我们的工作假设是SPHK1/S1P/ S1PR信号轴调节线粒体功能，这是病理学的基础原因 PASMC和PAEC的扩散以介导PAH发育。目标2：确定UPRMT抑制对血管重塑和HPH发育的影响。我们的工作假设是缺氧诱导UPRMT在体内的激活，从而导致血管重塑和 pah。 AIM 3：确定肺血管细胞和线粒体之间是否进行协调的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的信号传导在UPRMT中，线粒体裂变和线粒体呼吸可促进血管重塑。