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TSP1-CD47 in Promotion of PAH-Associated Vasoconstriction and Vascular Overgrowth

TSP1-CD47 促进 PAH 相关血管收缩和血管过度生长

基本信息

批准号：
8294522
负责人：
Jeffrey S Isenberg
金额：
$ 31.96万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8294522
关键词：
Affect Anatomy Angiogenic Proteins Animals Binding Blood Platelets Blood Vessels Blood flow Bone Marrow Transplantation CD47 gene Cells Cessation of life Chronic Chronic lung disease Coupled Data Disease Effectiveness Endothelial Cells Experimental Models Failure Functional disorder Gap Junctions Gold Growth Growth Factor Heart Heart failure Human Hypertrophy Hypoxia In Vitro Inflammatory Interruption Knockout Mice Life Ligands Link Liver Location Lung Lung diseases Malignant Neoplasms Mediator of activation protein Molecular Monocrotaline Mus Nitric Oxide PDGFRB gene Pathogenesis Pathologic Pathway interactions Patients Physiological Platelet-Derived Growth Factor Play Pre-Clinical Model Principal Investigator Process Production Progressive Disease Proteins Proto-Oncogene Proteins c-akt Pulmonary Vascular Resistance Pulmonary artery structure Regulation Resistance Respiratory physiology Response Elements Role Second Messenger Systems Signal Pathway Signal Transduction Smooth Muscle Myocytes Source System Testing Therapeutic Effect Thrombospondin 1 Up-Regulation Vascular Diseases Vascular remodeling Vasoconstrictor Agents Vasodilation Vasodilator Agents Work autocrine base cell growth constriction cytokine gene function human NOS3 protein in vivo migration new therapeutic target novel prevent promoter pulmonary arterial hypertension pulmonary artery endothelial cell receptor response second messenger stem therapeutic target vascular smooth muscle cell proliferation vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries marked by a progressive increase in pulmonary vascular resistance, leading to right heart failure and ultimately death. An imbalance between vasoconstriction and vasodilation coupled with vascular remodeling and overgrowth are hallmarks of PAH. Nitric oxide (NO) is known to play a protective role in PAH and endothelial failure and loss of NO signaling contribute to both human and experimental PAH. Recent work by the principal investigator has found that the matrix protein thrombospondin-1 (TSP1) blocks physiologic NO responses in vascular cells. Preliminary data suggests that TSP1, in binding to its necessary receptor CD47, inhibits activation of endothelial nitric oxide synthase (eNOS) and thus endothelial NO production, and that TSP1 and CD47 are dramatically upregulated in human and experimental PAH. Additional new data demonstrates that the TSP1-CD47 nexus stimulates vascular smooth muscle cell overgrowth in a PDGF-dependent manner in PAH. The central hypothesis to be tested in this proposal is that excessive TSP1 expression underlies PAH vasculopathy and that interaction with its cognate receptor, CD47, selectively regulates key second messenger pathways linked to microvascular vasoreactivity, growth, and remodeling. The present proposal will explore (i) the mechanisms behind upregulation of TSP1-CD47 in PAH, (ii) the implications this has on vascular tone and overgrowth and (iii) the effects that therapeutic interruption of the nexus has on preventing PAH and on ameliorating established disease.

描述(申请人提供)：肺动脉高压(PAH)是一种以肺血管阻力进行性增加为特征的小肺动脉疾病，导致右心衰竭并最终死亡。血管收缩和血管扩张之间的失衡，再加上血管重构和过度生长是PAH的特征。已知一氧化氮(NO)在PAH中起保护作用，内皮功能衰竭和NO信号的丢失导致人和实验性PAH。主要研究人员最近的工作发现，基质蛋白血栓反应蛋白-1(TSP1)阻断了血管细胞的生理性NO反应。初步数据表明，TSP1与其必需的受体CD47结合，抑制内皮型一氧化氮合酶(ENOS)的激活，从而抑制内皮细胞NO的产生，TSP1和CD47在人和实验性PAH中显著上调。更多的新数据表明，TSP1-CD47网络以PDGF依赖的方式刺激PAH中的血管平滑肌细胞过度生长。在这项建议中要检验的中心假设是，TSP1的过度表达是PAH血管病变的基础，并且与其同源受体CD47的相互作用选择性地调节与微血管反应性、生长和重塑相关的关键第二信使通路。本提案将探讨(I)在PAH中TSP1-CD47上调背后的机制，(Ii)这对血管张力和过度生长的影响，以及(Iii)神经节治疗中断在预防PAH和改善既定疾病方面的效果。