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The Transmembrane Protein Disulfide Isomerase TMX1 Negatively Regulates Thrombosis

跨膜蛋白二硫键异构酶 TMX1 负向调节血栓形成

基本信息

批准号：
10586515
负责人：
DAVID W ESSEX
金额：
$ 71.45万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-15 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586515
关键词：
Address Agonist Antibodies Anticoagulants Binding Blood Cells Blood Platelets Blood Vessels Blood coagulation COVID-19 Clot retraction Coagulation Process Cysteine Disease ERp57 Endothelial Cells Endothelium Enzymes Equilibrium Event Extracellular Protein Family Fibrin Fibrinogen Generations Hemorrhage Hemostatic function Human Immune checkpoint inhibitor Injury Integral Membrane Protein Integrins Isomerism Knockout Mice Lasers Mass Spectrum Analysis Mediating Membrane Modeling Molecular Conformation Morbidity - disease rate Mus Myocardial Infarction Pathway interactions Phosphatidylserines Platelet Activation Platelet Aggregation Inhibition Platelet aggregation Protein Disulfide Isomerase Proteins Recombinants Regulation Role Signal Transduction Site Stroke Sulfhydryl Compounds Surface Techniques Thrombosis Thrombus United States Vascular System Wild Type Mouse Work acute coronary syndrome disulfide bond disulfide bond reduction endoplasmic reticulum glycoprotein p72 extracellular in vivo insight member mortality mouse model novel oxidation platelet function prevent receptor translocase vascular injury

项目摘要

The control of platelet function and coagulation is a fine balance between activation and inhibitory mechanisms. Platelets become rapidly activated by multiple receptors agonists and have a central role in thrombosis in acute coronary syndromes, and other disease states. Similarly, naturally occurring anticoagulants are critical in preventing fibrin generation and thrombosis. Fivemembers of theprotein disulfide isomerase (PDI) family of enzymes, PDI, ERp57, ERp5, ERp72 and ERp46 potentiate activation of IIb3 and thrombosis.We discovered atransmembrane member of the PDI family found to inhibit activation of IIb3 and member of the PDI family in platelets, TMX1, which thrombosis. TMX1 is the first acts by a novel mechanism of oxidizing thiols to disulfide bonds and is the last checkpoint inhibitor of the platelet activation pathways that lead to conformational changes in IIb3 and fibrinogen binding. The prothrombotic PDIs are secreted from platelets and endothelial cells and support fibrin generation at the site of vascular injury. We found that TMX1 is expressed on platelets and endothelial cells but, negatively procoagulant in contras to the other PDIs, TMX1 regulates fibrin generation. One mechanism by which TMX1 inhibits coagulation is by limiting the effect of endothelial cells and platelets. We propose to study t vascular TMX1 as a dual negative regulator of platelets and coagulation by addressing the following Specific Aims. We will characterize 1. the role of TMX1 in thrombus formation; 2. the mechanism of inhibition of IIb3 activation by TMX1; 3. the effect of TMX1 on the other platelet PDIs, and on other platelet surface substrates. A principal technique used will be the laser-induced injury model of thrombosis. We will study the mechanism by which TMX1 negatively regulates coagulation. To determine the underlying mechanisms by which TMX1 inhibits platelet function we will integrate a platelet knockout mouse model with mass spectrometry-based identification of functional cysteines. This proposal will determine the mechanisms by which TMX1 works, and how TMX1 counterbalances the PDI enzymes that support activation of IIb3. Characterization of the negative regulatory role of TMX1 will provide novel insight into how the network of PDI enzymes regulate thrombosis. Studies on how TMX1 maintains the balance between thrombosis and hemostasis will elucidate optimal ways to promote hemostasis and inhibit thrombosis and provide a basis for studying TMX1 in disease states.

血小板功能和凝血的控制是激活和抑制之间的良好平衡