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。与扰动和低流量区域（称为d-流量）相比，在与高剪切应力相关的稳定流量区域（称为s-流量）中，动脉粥样硬化减少。这一发现产生了这样的概念，即s-流是动脉粥样硬化保护和d-流是动脉粥样硬化促进，部分原因是引起内皮细胞（EC）功能障碍。以前，我们表明，s-流激活硫氧还蛋白-1（Trx 1）在EC中，减少表达的Trx 1相互作用蛋白（Txnip），并抑制肿瘤坏死因子（TNF）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机制。1)Txnip表达通过d-flow增加，并通过刺激VCAM-1表达促进EC的粘附表型。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Trx 1和Txnip易位到质膜，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，SHP 2，一种蛋白酪氨酸磷酸酶（PTP 2），被证明可以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的结合也激活了该途径（图1）。因此，我们的主要假设是Txnip，像NF-kB一样，刺激EC中的促存活和促炎途径。在提出的目标中，我们将确定将Txnip-Trx 1-TKR-Akt存活途径与Txnip-SHP 2-ASK 1炎症途径分开的机制。目的1：表明Trx-Txnip通过组装信号复合物和抑制PTPases来刺激TKR活化和存活。目的2：研究Txnip对SHP 2活性的调节作用及对ASK 1活性的亚细胞定位调节作用。目的3：显示d-flow改变Txnip表达和位置，抑制Trx 1活性并激活ASK 1。目的4：显示EC特异性Txnip敲除小鼠表现出改善的EC功能和减少的动脉粥样硬化。这些研究应该提供对流动抑制炎症的机制的深入了解，并促进限制动脉粥样硬化的治疗方法的发展。 公共卫生相关性：中风和心脏病发作是美国的主要死亡原因。诸如旁路手术和血管成形术的干预治疗急性事件，但是有有限的疗法来预防称为动脉粥样硬化的潜在疾病。我们已经发现，在动脉粥样硬化发展的部位，硫氧还蛋白相互作用蛋白在血管中增加。在这里，我们将集中在新的方法来抑制这种蛋白质的功能。阐明硫氧还蛋白相互作用蛋白调节血管功能的特异性途径将为开发新的治疗方法以预防动脉粥样硬化提供基础。