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Membrane Phospholipids: The Key Regulator 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：
8885418
负责人：
Vijaya Mohan Rao Lella
金额：
$ 36.25万
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 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8885418
关键词：
4 hydroxynonenal Acute myocardial infarction Affect Aldehydes Binding Biochemistry Blood Coagulation Factor Blood Vessels Blood coagulation Cell Surface Receptors Cell membrane Cell surface Cells Coagulants Coagulation Process Complex Data Dependency Development Disease Disulfides Endothelial Cells Equilibrium Event Excision Exhibits Factor VIIa Fatty Acids Generations Glycoproteins Health Hemorrhage Hemostatic Agents Hemostatic function Hydrolysis Inflammation Injury Integral Membrane Protein Interphase Cell Investigation Ischemic Stroke Knowledge Lipid Peroxidation Liposomes MAP Kinase Gene MAPK14 gene Maintenance Malignant Neoplasms Mechanics Mediating Membrane Membrane Lipids Membrane Microdomains Metabolism Molecular Oxidative Stress Pathogenesis Pathway interactions Phosphatidylserines Phospholipids Plasma Play Prevention strategy Process Protein Disulfide Isomerase Reaction Reactive Oxygen Species Regulation Role Signal Pathway Signal Transduction Sphingomyelins Stimulus Sulfhydryl Compounds Surface System Testing Thioredoxin Thromboplastin Thrombosis Thrombus Unstable angina cell injury cell type cofactor design effective therapy encryption improved insight macrophage novel novel therapeutics oxidation public health relevance research study response rho treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The coagulation cascade is initiated by binding of coagulation factor VIIa (FVIIa) to its cell surface receptor, tissue factor (TF). Tissue factor is essential for hemostasis, but the aberrant expression or activation of TF leads to thrombosis, the precipitating event in acute myocardial infarction, unstable angina, and ischemic stroke. It also contributes to inflammation and cancer. Therefore, the proper regulation of TF expression and the activity is critical for not only to maintenance of the hemostatic balance, but also for health in general. Interestingly, the majority of TF on cell surfaces exists in a cryptic state, i.., with no or little coagulant activity, despite forming complex with FVIIa. A stimulus is required fo cryptic TF to become procoagulant active form. A variety of cellular alterations transforms cryptic TF to coagulant active TF. Our recent studies show that 4- hydoxynonenal (HNE), one of the most abundant and bioactive species produced by the lipid peroxidation, activates TF in monocytic and endothelial cells. At present, it is unclear how the coagulant active TF differs from the cryptic form or mechanics involved in TF encryption and decryption. It is unknown, at present, whether phospholipids present in the outer leaflet of plasma membrane play a critical role in maintaining TF in the cryptic state. Of all the proposed mechanisms, externalization of anionic phospholipids at the outer leaflet of plasma membrane following cell activation appears to be the main mechanism for transformation of the cryptic TF into active TF. However, other mechanisms, such as protein disulfide isomerase (PDI)-mediated thiol-disulfide exchange reactions, may also play an important role in TF activation in certain cell types. Mechanisms responsible for maintaining TF in a cryptic state in naive cells and molecular pathways responsible for exposure of anionic phospholipids in response to pathophysiologically relevant stimuli are unknown. The following specific aims are designed to fill these gaps of the knowledge on the regulation of TF activity at the cell surface. Aim 1: Test a novel hypothesis that high sphingomyelin content in the outer leaflet of the plasma membrane is responsible for maintaining TF in its cryptic state at the cell surface. Here, we will also test that the hydrolysi of sphingomyelin in the plasma membrane plays a key role in TF decryption; Aim 2: Elucidate signaling mechanism(s) involved in externalization of phosphatidylserine and TF activation by HNE, and ascertain contribution of PDI-mediated thiol-disulfide exchange pathways and lipid raft integrity in this process. To strengthen observations made in cell systems, and to have better understanding of how cell membrane lipids influence TF activity, we will also perform additional studies with purified TF incorporated into defined liposomes. The data obtained from the proposed studies will provide new insights into understanding of the regulation of TF activity on cell surfaces. Overall, the knowledge gained from the proposed studies will be helpful in understanding the pathogenesis of thrombotic disorders and will be useful in designing better treatment strategies for both thrombotic and hemorrhagic diseases.