SOCS-1 and endothelial dysfunction in graft arteriosclerosis

SOCS-1 与移植动脉硬化中的内皮功能障碍

基本信息

批准号：
7491182
负责人：
WANG MIN
金额：
$ 38.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7491182
关键词：
Acetylcholine Affect Allografting Angioplasty Antibodies Aorta Apolipoprotein E Appearance Arteries Arteriosclerosis Atherectomy Atherosclerosis Binding Biological Assay Biological Availability Blood Vessels Bos taurus Cattle Cell physiology Cells Chronic Clinical Research Complex Coronary artery Cytokine Inducible SH2-Containing Protein Data Defect Development Doctor of Medicine Doctor of Philosophy Endothelial Cells Event Failure Functional disorder Gene Expression Genes Genetic Growth Factor Heart Transplantation Human Hyperplasia Impairment Inflammatory Inflammatory Response Insulin Insulin-Like Growth Factor I JUN gene Jordan Knock-out Laboratories Link MAP3K5 gene Mediating Mediator of activation protein Messenger RNA Microsurgery Mitogens Modeling Molecular Profiling Mus N-terminal PTPN11 gene Pathogenesis Pathway interactions Phase Phosphorylation Phosphotransferases Phosphotyrosine Physiology Principal Investigator Production Progress Reports Protein Biosynthesis Protein Overexpression Protein Tyrosine Phosphatase Proteins RNA Interference Recruitment Activity Relaxation Reporting Research Personnel Rest Role SCID Beige Mouse Signal Transduction Signaling Protein Site Smooth Muscle Myocytes Specimen Stimulus Suppressor of Cytokine Signaling Family Protein T-Lymphocyte TNF gene Testing Transgenic Mice Transplantation Tyrosine Tyrosine Phosphorylation Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factors Viral Vector Work Xenograft Model Xenograft procedure base cytokine genetic regulatory protein graft failure heart allograft human NOS3 protein human disease innovation member morphometry mouse model novel therapeutics prevent programs receptor response restenosis shear stress src Homology Region 2 Domain stress-activated protein kinase 1 transduction efficiency

项目摘要

Graft arteriosclerosis (GA), defined as progressive loss of lumen in allograft conduit arteries, is the major cause of chronic cardiac allograft failure. Several recent lines of evidence have implicated the cytokine IFN-y as a pro-arteriosclerotic factor and that a key functional effect of IFN-Y on endothelial cells (EC) is an early impairment of EC-dependent relaxation which occurs prior to and is causally linked to smooth muscle cell (SMC) accumulation. Specifically, my colleagues have reported IFN-y-dependent reduction in the function/expression of endothelial nitric oxide synthase (eNOS) in graft EC. Interestingly, IFN-y by itself does not affect eNOS. It acts in concert with INF, another proinflammatoy cytokine, to reduce eNOS expression and NO release by EC. However, the mechanism by which IFN-Y and TNF synergistically reduce NO production by EC is not known, and is the subject of this project. Our data suggest that SOCS1, a member of suppressor of cytokine signaling proteins, is a critical mediator in IFN-y and TNF-induced EC dysfunction. We propose the following hypotheses: 1). In resting (and IFN-y-exposed) EC, SOCS1 binds to inactive (tyrosine phosphorylated) ASK1 leading to mutual degradation of both SOCS1 and ASK1. 2). In response to TNF, ASK1 is dissociated from SOCS1 leading to activation of ASK1-JNK signaling which in turn phosphorylates and activates SOCS1. 3). Activated SOCS1 and ASK1-JNK independently and synergistically inhibit growth factors (e.g. VEGF and IGF-1 )-mediated NO release leading to EC dysfunction and GA progression. We propose the following specific aims to test our hypothesis: 1) Determine the mechanism(s) by which SOCS1 induces ASK1 degradation in EC and how IFN-y and TNF modify this response. 2) Determine the mechanism(s) by which SOCS1 impairs NO function. 3) Determine the role of SOCS1 in EC function in allograft and xenograft models. These studies should facilitate the development of new therapeutic approaches to control GA and graft failure as well as other vascular diseases such as atherosclerosis.

移植动脉硬化（GA），定义为同种异体移植物导管动脉管腔进行性丧失，是主要的疾病慢性同种异体心脏移植衰竭的原因。最近的一些证据表明细胞因子 IFN-y 作为一种促动脉硬化因子，IFN-Y 对内皮细胞 (EC) 的关键功能作用是早期 EC依赖性松弛的损害发生在平滑肌细胞之前并且与平滑肌细胞有因果关系（SMC）积累。具体来说，我的同事报告了 IFN-γ 依赖性的减少移植物 EC 中内皮一氧化氮合酶 (eNOS) 的功能/表达。有趣的是，IFN-y 本身确实不影响 eNOS。它与另一种促炎细胞因子 INF 协同作用，减少 eNOS 表达和 EC 释放的 NO。然而，IFN-Y和TNF协同减少NO的机制 EC 的生产未知，并且是该项目的主题。我们的数据表明 SOCS1 的成员细胞因子信号蛋白的抑制因子，是 IFN-γ 和 TNF 诱导的 EC 功能障碍的关键介质。我们提出以下假设：1）。在静息（和 IFN-γ 暴露）EC 中，SOCS1 与非活性结合（酪氨酸磷酸化）ASK1 导致 SOCS1 和 ASK1 相互降解。 2）。作为回应 TNF、ASK1 从 SOCS1 解离，导致 ASK1-JNK 信号传导激活，进而激活 ASK1-JNK 信号传导磷酸化并激活 SOCS1。 3）。独立激活 SOCS1 和 ASK1-JNK，协同抑制生长因子（例如 VEGF 和 IGF-1）介导的 NO 释放，导致 EC 功能障碍和 GA 进展。我们提出以下具体目标来检验我们的假设：1）确定 SOCS1 在 EC 中诱导 ASK1 降解的机制以及 IFN-y 和 TNF 如何改变这种机制回复。 2) 确定SOCS1 损害NO 功能的机制。 3）确定角色 SOCS1 在同种异体移植和异种移植模型中的 EC 功能中的作用。这些研究应有助于发展控制 GA 和移植失败以及其他血管疾病（例如动脉粥样硬化。