权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结/文摘