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：
8024878
负责人：
Bradford C Berk
金额：
$ 38.41万
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 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8024878
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 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

DESCRIPTION (provided by applicant): 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- alpha 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. PUBLIC HEALTH RELEVANCE: Strokes and heart attacks are the leading cause of death in the US. Interventions such as bypass surgery and angioplasty treat acute events, but there are limited therapies to prevent the underlying disease termed atherosclerosis. We have found that thioredoxin interacting protein is increased in blood vessels at sites where atherosclerosis develops. Here we will focus on novel approaches to inhibit the function of this protein. Elucidating the specific pathways by which thioredoxin interacting protein modulates vessel function will provide the basis to develop new therapies to prevent atherosclerosis.

描述（由申请人提供）：炎症有助于动脉粥样硬化的发展。与受干扰和低流量（称为 d 流）的区域相比，与高剪切应力相关的稳定流量区域（称为 s 流）的动脉粥样硬化减少。这一发现得出了这样的概念：s 流具有动脉粥样硬化保护作用，而 d 流则通过引起内皮细胞 (EC) 功能障碍而促进动脉粥样硬化。之前我们发现 s-flow 激活 EC 中的硫氧还蛋白-1 (Trx1)，降低 Trx1 相互作用蛋白 (Txnip) 的表达，并抑制肿瘤坏死因子 (TNF) 信号传导。多项研究结果表明，Txnip 依赖性信号传导代表了一种独特的动脉粥样硬化促进机制。 1) d-flow 增加 Txnip 表达，并通过刺激 VCAM-1 表达促进 EC 的粘附表型。 2) Txnip 特异性抑制 Trx1 功能并导致 EC 中的氧化应激。 3) Txnip 是 EC 中 TNF-α 介导的 JNK 和 caspase-3 激活所必需的。 4) 令人兴奋的初步数据表明，TNF 导致 Trx1 和 Txnip 易位至质膜并刺激酪氨酸激酶受体 (TKR) 信号通路，通过 Akt 激活抑制细胞凋亡（图 1）。最近，SHP2（一种蛋白酪氨酸磷酸酶 (PTPase)）被证明可以刺激细胞凋亡信号调节激酶 (ASK1)-JNK-VCAM1 通路。 5）我们的数据表明，Txnip 与 SHP2 结合也会激活该途径（图 1）。因此，我们的主要假设是 Txnip 与 NF-kB 一样，刺激 EC 中的促生存和促炎症途径。在拟议的目标中，我们将确定将 Txnip-Trx1-TKR-Akt 生存途径与 Txnip-SHP2-ASK1 炎症途径分开的机制。目标 1：证明 Trx-Txnip 通过组装信号复合物和抑制 PTPase 来刺激 TKR 激活和存活。目标 2：表明 Txnip 调节 SHP2 活性和调节 ASK1 活性的亚细胞位置。目标 3：表明 d-flow 改变 Txnip 表达和位置，抑制 Trx1 活性并激活 ASK1。目标 4：表明 EC 特异性 Txnip 敲除小鼠表现出 EC 功能改善和动脉粥样硬化减少。这些研究应该深入了解血流抑制炎症的机制，并促进限制动脉粥样硬化的治疗方法的开发。公共卫生相关性：中风和心脏病是美国的主要原因。搭桥手术和血管成形术等干预措施可以治疗急性事件，但预防动脉粥样硬化这一潜在疾病的疗法有限。我们发现，在动脉粥样硬化发生部位的血管中，硫氧还蛋白相互作用蛋白增加。在这里，我们将重点关注抑制这种蛋白质功能的新方法。阐明硫氧还蛋白相互作用蛋白调节血管功能的具体途径将为开发预防动脉粥样硬化的新疗法提供基础。