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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：
8208041
负责人：
Bradford C Berk
金额：
$ 38.63万
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/8208041
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.

抽象/总结