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Flow Responsive Mediators of Inflammation and Survival

炎症和生存的流量响应介质

基本信息

批准号：
8588987
负责人：
Bradford C Berk
金额：
$ 37.85万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2011-01-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8588987
关键词：
Abbreviations Acute Adhesions Adhesives Angioplasty Antioxidants Apolipoprotein E Apoptosis Area Atherosclerosis Binding Biological Availability Blood Vessels Blood flow Bypass Cause of Death Cell Nucleus Cell Survival Cell membrane Cell physiology Cells Cellular Stress Chemotactic Factors Complex Cytoplasm Data Development Disease Endothelial Cells Environment Event Exhibits Extracellular Protein Fluorescence Functional disorder G6PD gene Glucosephosphate Dehydrogenase Goals Human Immunohistochemistry Inflammation Inflammation Mediators Inflammatory Intervention JUN gene Knockout Mice Ligands Location MAP3K5 gene MAPK8 gene Macrophage Activation Mediating Metalloproteases Mitogen-Activated Protein Kinases Mus Myocardial Infarction N-terminal NF-kappa B Natriuretic Peptides Nitric Oxide Nuclear Operative Surgical Procedures Oxidation-Reduction Oxidative Stress PTPN11 gene Pathology Pathway interactions Pattern Phenotype Phosphotransferases Process Production Proliferating Prostaglandins I Protein Binding Protein Deficiency Protein Kinase Protein Tyrosine Phosphatase Proteins Publishing Reactive Oxygen Species Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Role Rupture Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Src homology 2 domain-containing, transforming protein 1 Staging Stroke Superoxide Dismutase Thioredoxin Tumor Necrosis Factor-alpha Tyrosine Phosphorylation Umbilical vein Vascular Cell Adhesion Molecule-1 abstracting atheroprotective base biological adaptation to stress caspase-3 clinically significant cytokine glutaredoxin improved insight macrophage monocyte novel novel strategies novel therapeutic intervention oxidized low density lipoprotein prevent protein expression protein function protein tyrosine phosphatase 1B response scaffold shear stress therapeutic development therapy development

项目摘要

Abstract/Summary Inflammation contributes to development of atherosclerosis. Atherosclerosis is decreased in regions of steady flow associated with high shear stress (termed s-flow), compared to regions of disturbed and low flow (termed d-flow). This finding has yielded the concept that s-flow is atheroprotective and d-flow is atheropromoting, in part by causing endothelial cell (EC) dysfunction. Previously we showed that s-flow activated thioredoxin-1 (Trx1) in EC, decreased expression of the Trx1 interacting protein (Txnip), and inhibited tumor necrosis factor (TNF) signaling. Several findings indicate that Txnip-dependent signaling represents a unique atheropromoting mechanism. 1) Txnip expression is increased by d-flow and promotes the adhesive phenotype of EC, by stimulating VCAM-1 expression. 2) Txnip specifically inhibits Trx1 function and contributes to oxidative stress in EC. 3) Txnip is required for TNF- mediated JNK and caspase-3 activation in EC. 4) Exciting preliminary data show that TNF causes Trx1 and Txnip to translocate to the plasma membrane and stimulate a tyrosine kinase receptor (TKR) signaling pathway that inhibits apoptosis via Akt activation (Fig. 1). Recently, SHP2, a protein tyrosine phosphatase (PTPase), was shown to stimulate the Apoptosis Signal-regulated Kinase (ASK1)-JNK-VCAM1 pathway. 5) Our data show that Txnip binding to SHP2 also activates this pathway (Fig. 1). Thus our major hypothesis is Txnip, like NF-kB, stimulates both pro-survival and pro-inflammatory pathways in EC. In the proposed aims we will identify mechanisms to separate the Txnip-Trx1-TKR-Akt survival pathway from the Txnip-SHP2-ASK1 inflammation pathway. Aim 1: Show that Trx-Txnip stimulates TKR activation and survival by assembling signal complexes and inhibiting PTPases. Aim 2: Show that Txnip regulates SHP2 activity and subcellular location modulating ASK1 activity. Aim 3: Show that d-flow alters Txnip expression and location inhibiting Trx1 activity and activating ASK1. Aim 4: Show that EC-specific Txnip knockout mice exhibit improved EC function and decreased atherosclerosis. These studies should provide insight into mechanisms by which flow inhibits inflammation and facilitate development of therapeutic approaches to limit atherosclerosis.

摘要/概要炎症有助于动脉粥样硬化的发展。动脉粥样硬化在稳定的区域减少，与高剪切应力相关的流动（称为s流）相比，扰动和低流动（称为 D-流）。这一发现产生了这样的概念，即s流是动脉粥样硬化保护的，d流是动脉粥样硬化促进的，部分原因是导致内皮细胞（EC）功能障碍。之前我们发现s-flow激活硫氧还蛋白-1 在EC中，Trx 1相互作用蛋白（Txnip）的表达降低，并且抑制肿瘤坏死因子（TNF）的表达。 (TNF)发信号。一些研究结果表明，Txnip依赖的信号转导代表了一种独特的动脉粥样硬化促进作用，机制1)TXNIP表达通过D-流增加，并促进粘附 EC表型，通过刺激VCAM-1的表达。2)Txnip特异性抑制Trx 1 功能，并有助于EC中的氧化应激。3)Txnip是TNF-α所必需的。介导JNK和caspase-3的激活。4)令人兴奋的初步数据显示， TNF导致Trx 1和Txnip易位到质膜并刺激细胞凋亡。酪氨酸激酶受体（TKR）信号通路，通过Akt抑制细胞凋亡激活（图1）。最近，SHP 2，一种蛋白酪氨酸磷酸酶（PTP 2），被显示刺激凋亡信号调节激酶（ASK 1）-JNK-VCAM 1 通路5)我们的数据显示，Txnip与SHP 2的结合也激活了这一途径（图1B）。 1）。因此，我们的主要假设是Txnip，像NF-kB一样，刺激促存活和促凋亡两者。 EC中的促炎途径。在拟议的目标中，我们将确定机制，将Txnip-Trx 1-TKR-Akt存活途径与Txnip-SHP 2-ASK 1分离炎症通路目标1：表明Trx-Txnip刺激TKR激活，通过组装信号复合物和抑制PTPases来存活。目的2：显示Txnip调节SHP 2 活性和亚细胞定位调节ASK 1活性。目的3：显示d-流改变Txnip表达，抑制Trx 1活性和激活ASK 1的位置。目的4：显示EC特异性Txnip敲除小鼠表现出改善EC功能和减少动脉粥样硬化。这些研究应该提供深入了解机制通过这种流动抑制炎症并促进治疗方法的发展，动脉粥样硬化