Membrane Phospholipids: The Key Regulators of Tissue Factor Encryption/Decryption

膜磷脂：组织因子加密/解密的关键调节剂

基本信息

批准号：
10153855
负责人：
Vijaya Mohan Rao Lella
金额：
$ 45.7万
依托单位：
UNIVERSITY OF TEXAS HLTH CTR AT TYLER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153855
关键词：
Acute Acute myocardial infarction Address Antigens Atherosclerosis Biology Blood Blood Cells Blood Coagulation Disorders Blood Coagulation Factor Blood Coagulation Factor VII Blood coagulation Cell membrane Cell surface Cells Coagulants Coagulation Process Complex Data Development Diabetes Mellitus Disease Down-Regulation Endothelial Cells Ensure Enzyme Inhibitor Drugs Enzymes Epithelial Cells Equilibrium Event Factor IX Factor VIIa Factor X Generations Glycoproteins Health Hemorrhage Hemostatic Agents Hemostatic function Hydrolysis Infection Inflammation Inflammatory Interphase Cell Intervention Ischemic Stroke Kinetics Knockout Mice Knowledge Lead Lipoxygenase Maintenance Malignant Neoplasms Mediating Membrane Membrane Microdomains Metabolism Molecular Conformation Morbidity - disease rate Mus Pathogenesis Pathway interactions Pericytes Pharmacology Phospholipids Plasma Play Preventive Process Proteins Publishing Regulation Research Role Sepsis Sphingomyelinase Sphingomyelins Stimulus Structure Testing Thromboplastin Thrombosis Thrombus Transgenic Mice Unstable angina Vascular Endothelial Cell Wild Type Mouse acid sphingomyelinase atherogenesis cell injury cell type cofactor cohesion encryption experimental study in vivo inhibitor/antagonist insight macrophage microvesicles monocyte mortality mouse model novel novel therapeutics overexpression prevent response sphingomyelin synthase systemic inflammatory response thrombotic transcription factor vascular injury

项目摘要

Upon vascular injury, plasma clotting factor VII (FVII) along with traces of activated FVII (FVIIa) come into contact with the cofactor tissue factor (TF), which is expressed constitutively in cells within the vessel wall. Complex formation of FVIIa with TF results in a marked enhancement of the catalytic activity of FVIIa and triggers TF-mediated blood coagulation. Certain disease conditions induce TF expression in circulating blood cells and vascular endothelial cells and thus allow direct contact between circulating blood and TF that leads to thrombosis. While TF-mediated blood coagulation is essential to maintain hemostasis, the aberrant activation of TF-mediated blood coagulation leads to thrombosis, the precipitating event in acute myocardial infarction, ischemic stroke, and sepsis. Therefore, the proper regulation of TF expression and the activity is critical for not only to the maintenance of the hemostatic balance but also for health in general. Typically, most of the TF expressed in cells stays encrypted with very little procoagulant activity that is sufficient to achieve hemostasis but not to cause intravascular coagulation. Cellular injury enhances TF procoagulant activity greatly without altering TF antigen levels, i.e., transforming cryptic TF to prothrombotic TF. TF procoagulant activity in cells is controlled dynamically by a variety of post-translational mechanisms. Our recent studies revealed that sphingomyelin (SM) in the outer leaflet of the plasma membrane is responsible for maintaining TF in an encrypted state and that hydrolysis of SM activates TF and releases TF+ microvesicles (MVs). SM metabolism is altered in many disease settings, including atherosclerosis, diabetes, sepsis, and cancer, the same disease settings that induce aberrant activation of TF. The current proposal is built on the above novel findings and proposes to investigate the pathophysiologic relevance of SM metabolism in regulation of TF- mediated hemostasis, thrombosis, and inflammation. Aim 1 focuses on elucidating mechanisms by which SM metabolism regulates TF procoagulant activity, whereas Aim 2 investigates whether SM metabolism influences hemostasis and thrombosis. Experiments proposed in Aim 3 will test the hypothesis that acute inflammation-induced alterations in SM metabolism play a key role in TF activation and TF-mediated coagulopathy. Aim 4 focuses on investigating whether altered SM metabolism contributes to inflammation via the regulation of TF activity. In the proposed studies, we will manipulate SM levels in macrophages, endothelial cells, and other cell types by the overexpression or down regulation of various enzymes involved in the SM metabolism or using specific pharmacological inhibitors of these enzymes. We will employ various knock-out mice with altered SM metabolism and murine models of hemostasis and thrombosis to investigate the pathophysiologic relevance of the newly identified mechanism. Our proposed studies will lead to a paradigm shift in our understanding of how TF-mediated coagulation is activated in various disease settings. They may also lead to the development of novel, targeted interventions to prevent thrombosis.

血管损伤后，血浆凝血因子 VII (FVII) 以及微量活化的 FVII (FVIIa) 进入与辅因子组织因子（TF）接触，该因子在血管壁内的细胞中组成型表达。 FVIIa与TF形成复合物导致FVIIa和TF的催化活性显着增强触发 TF 介导的血液凝固。某些疾病会诱导循环血液中的 TF 表达细胞和血管内皮细胞，从而允许循环血液和 TF 直接接触，从而导致至血栓形成。虽然 TF 介导的凝血对于维持止血至关重要，但异常的 TF 介导的凝血激活导致血栓形成，这是急性心肌梗塞的诱发事件梗塞、缺血性中风和败血症。因此，对TF表达和活性的适当调节是不仅对于维持止血平衡至关重要，而且对于整体健康也至关重要。通常，大多数细胞中表达的 TF 保持加密状态，几乎没有促凝血活性，足以实现止血但不引起血管内凝血。细胞损伤增强 TF 促凝血活性大大不改变 TF 抗原水平，即将隐性 TF 转化为促血栓 TF。 TF促凝剂细胞中的活性由多种翻译后机制动态控制。我们最近的研究揭示质膜外叶中的鞘磷脂（SM）负责维持 TF 处于加密状态，SM 水解会激活 TF 并释放 TF+ 微泡 (MV)。 SM 在许多疾病中，新陈代谢都会发生改变，包括动脉粥样硬化、糖尿病、败血症和癌症，诱导 TF 异常激活的相同疾病环境。目前的提案是建立在上述小说的基础上的研究结果并建议研究 SM 代谢在 TF- 调节中的病理生理学相关性介导止血、血栓形成和炎症。目标 1 侧重于阐明 SM 的机制代谢调节 TF 促凝血活性，而 Aim 2 研究 SM 代谢是否影响止血和血栓形成。目标 3 中提出的实验将检验以下假设：急性炎症诱导的 SM 代谢改变在 TF 激活和 TF 介导中发挥关键作用凝血病。目标 4 重点研究 SM 代谢的改变是否通过以下方式导致炎症： TF 活性的调节。在拟议的研究中，我们将操纵巨噬细胞中的 SM 水平，内皮细胞和其他细胞类型通过所涉及的各种酶的过度表达或下调 SM 代谢或使用这些酶的特定药理学抑制剂。我们将聘请各种 SM代谢改变的基因敲除小鼠和止血和血栓形成的小鼠模型进行研究新发现的机制的病理生理学相关性。我们提出的研究将导致我们对 TF 介导的凝血如何在各种疾病环境中被激活的理解发生了范式转变。它们还可能导致开发新的、有针对性的干预措施来预防血栓形成。