Flow Responsive Mediators of Inflammation and Survival

炎症和生存的流量响应介质

• 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
• 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

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。与流动障碍和低流量区域相比，与高剪切应力（称为S-Flow）相关的稳定流动区域的动脉粥样硬化降低（称为D-Flow）。这一发现得出了这样一个概念，即S-Flow是动脉保护性的，而D-Flow则是动脉粥样硬化的，部分原因是导致内皮细胞（EC）功能障碍。先前我们表明，S-Flow在EC中激活了硫氧还蛋白-1（TRX1），降低了TRX1相互作用蛋白（TXNIP）的表达，并抑制了肿瘤坏死因子（TNF）信号传导。几个发现表明TXNIP依赖性信号传导代表了独特的动脉振动机制。 1）通过d-flow增加TxNIP表达，并通过刺激VCAM-1表达来促进EC的粘附表型。 2）TXNIP特异性抑制TRX1功能，并有助于EC中的氧化应激。 3）TXNIP是tnf- alpha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转移到质膜并刺激酪氨酸激酶受体（TKR）信号通路，该信号通过AKT激活抑制凋亡（图1）。最近，SHP2是一种蛋白酪氨酸磷酸酶（PTPase），可刺激凋亡信号调节激酶（Ask1）-JNK-VCAM1途径。 5）我们的数据表明，TXNIP与SHP2的结合也激活了这一途径（图1）。因此，我们的主要假设是TXNIP，例如NF-KB，刺激了EC中的促生存和促炎途径。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。 AIM 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。 AIM 2：证明TXNIP调节SHP2活性和亚细胞位置调节ASK1活动。 AIM 3：证明D-Flow会改变TXNIP的表达和抑制TRX1活性并激活Ask1的位置。 AIM 4：表明EC特异性TXNIP敲除小鼠具有改善的EC功能并降低动脉粥样硬化。这些研究应提供有关流动抑制炎症并促进治疗方法以限制动脉粥样硬化的机制的洞察力。 公共卫生相关性：中风和心脏病发作是美国死亡的主要原因。旁路手术和血管成形术等干预措施治疗急性事件，但预防潜在疾病被称为动脉粥样硬化的疗法有限。我们发现，在动脉粥样硬化发展的部位的血管中，硫氧还蛋白相互作用的蛋白质增加。在这里，我们将重点介绍抑制该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特定途径将为预防动脉粥样硬化的新疗法提供基础。