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

• 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
• 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

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.

移植物动脉硬化（GA），定义为同种异体移植管道动脉管腔的进行性丢失，是移植物动脉硬化的主要原因。 慢性心脏移植失败的原因最近的一些证据表明细胞因子IFN-γ 作为促动脉炎因子，IFN-γ对内皮细胞（EC）的关键功能作用是早期血管内皮细胞（EC）的凋亡。 在平滑肌细胞之前发生并与平滑肌细胞有因果关系EC依赖性舒张受损 (SMC)积累具体来说，我的同事已经报道了IFN-γ依赖性的减少， 内皮型一氧化氮合酶（eNOS）在移植EC中的功能/表达。有趣的是，IFN-γ本身 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 EC释放NO。然而，IFN-Y和TNF协同降低NO的机制 欧盟委员会的生产情况尚不清楚，这是本项目的主题。我们的数据表明，SOCS 1，一个成员 细胞因子信号传导蛋白的抑制因子是IFN-γ和TNF诱导的EC功能障碍中的关键介质。 我们提出以下假设：1）。在静息（和IFN-γ暴露）EC中，SOCS 1结合失活的 （酪氨酸磷酸化）ASK 1导致SOCS 1和ASK 1的相互降解。2）。响应于 TNF、ASK 1与SOCS 1解离，导致ASK 1-JNK信号传导激活，进而激活 磷酸化并激活SOCS 1。3）。独立激活SOCS 1和ASK 1-JNK， 协同抑制生长因子（例如VEGF和IGF-1）介导的导致EC功能障碍的NO释放 GA的进展。我们提出以下具体目标来检验我们的假设：1）确定 SOCS 1诱导EC中ASK 1降解的机制以及IFN-γ和TNF如何对此进行修饰 反应2)确定SOCS 1损害NO功能的机制。3)确定的作用 SOCS 1在同种异体移植和异种移植模型中的EC功能。这些研究应有助于发展 新的治疗方法来控制GA和移植失败以及其他血管疾病， 动脉粥样硬化