The Biochemistry and Physiology of Platelet TFPI

血小板 TFPI 的生物化学和生理学

• 批准号: 7879337
• 负责人: Susan Antone Maroney
• 金额: $ 12.52万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879337
• 关键词: Actins; Animals; Anticoagulants; Area; Atherosclerosis; Biochemical; Biochemistry; Blood; Blood Clot; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Blood coagulation; Brain; Breeding; Cerebrum; Cessation of life; Coagulation Process; Collagen; Complex; Coronary; Cytoplasmic Granules; Cytoskeleton; Data; Deep Vein Thrombosis; Deposition; Development; Development Plans; Discipline; Disease; Down-Regulation; Embryo; Embryonic Development; Endothelium; Equilibrium; Evaluation; Fetal Liver; Fibrin; Fractionation; Funding; Goals; Growth; Hematology; Hemorrhage; Hemostatic Agents; Hepatic; Immunoelectron Microscopy; In Vitro; Injury; Intravascular Thrombus Formation; Investigation; Leukocytes; Life; Link; Liver; Location; Longevity; Lysosomes; Maintenance; Malignant Neoplasms; Megakaryocytes; Membrane; Membrane Microdomains; Mentors; Messenger RNA; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Paper; Pathology; Patients; Peripheral Vascular Diseases; Phenotype; Physiological; Physiology; Play; Principal Investigator; Process; Production; Proteins; Public Health; Publishing; Pulmonary Embolism; RNA Splicing; Research; Research Institute; Research Personnel; Role; Scientist; Series; Source; Stroke; Surface; System; TFPI; Testing; Thrombin; Thromboplastin; Thrombosis; Thrombus; Training; Visit; Wisconsin; abstracting; base; career development; design; experience; in vivo; inhibitor/antagonist; lectures; liver transplantation; mRNA Precursor; medical schools; mouse model; prevent; programs; research study; tissue-factor-pathway inhibitor 2

DESCRIPTION (provided by applicant): Tissue factor pathway inhibitor (TFPI) is the major inhibitor of the tissue factor/factor Vila (TF/Vlla) catalytic complex that initiates blood coagulation. Therefore, TFPI is a potent anticoagulant protein. The amount of TF within the vasculature system increases in diseases such as atherosclerosis and cancer producing intravascular thrombosis that can result in common and severe diseases such as heart attack, stroke and pulmonary embolism. The long term goal of our proposed studies is to understand the role of TFPI produced by megakaryocytes and expressed on the surface of activated platelets in controlling intravascular TF activity. We hypothesize that platelet TFPI is optimally located and concentrated in order to down-regulate TF activity within a growing blood clot. Thereby, it prevents the formation of blood clots that totally occlude the blood vessel and produce severe, potentially lethal, disease. This hypothesis is based on the following: 1) circulating TF in the blood is a major contributor to clot formation and growth; 2) TFPI is the only physiological inhibitor of TF; 3) platelets are the major cellular component of clot formation; 4) actin and TFPI co-localize within activated platelets; and 5) mice deficient in platelet TFPI have substantial amounts of fibrin deposition in their liver and brain that is not present in mice with platelet TFPI. The experiments proposed here will determine 1) the intracellular location of TFPI within quiescent platelets; 2) the biochemical mechanism(s) for transfer of TFPI to the surface of activated platelets; and 3) the physiological function(s) of platelet TFPI in an in vivo mouse model of TFPI deficiency. This proposal is part of a career development plan spanning 5 years. The career development plan includes additional training in the discipline of hematology, mouse pathology and embryogenesis. Continuous interactions with basic scientists at the Blood Research Institute (BRI) of the Blood Center of Wisconsin and the Medical College of Wisconsin will provide 1) access to experienced investigators with expertise in the areas of hematology, coagulation, and pathology, 2) production and evaluation of mouse models, 3) use of in vitro and in vivo systems to study coagulation, and 4) access to internationally and nationally recognized scientists through the visiting lecture series sponsored by the Blood Research Institute. These opportunities will provide additional support and mentoring as Dr. Maroney transitions to an independently funded investigator. RELEVANCE (Seeinstructions): This proposal is relevant to public health as it investigates the role platelet TFPI plays in the down-regulation of the clot forming activities of platelets. Investigation of these mechanisms will enhance our understanding of how platelets can form clots to prevent severe bleeding while controlling clot growth to prevent vessel occlusion that can result in stroke or heart attack or other potentially lethal diseases. (End of Abstract)

描述（由申请人提供）：组织因子途径抑制剂（TFPI）是启动血液凝固的组织因子/因子VIIa（TF/VIIa）催化复合物的主要抑制剂。因此，TFPI是一种有效的抗凝血蛋白。在动脉粥样硬化和癌症等疾病中，脉管系统内的 TF 量会增加，从而导致血管内血栓形成，从而导致心脏病、中风和肺栓塞等常见和严重疾病。我们提出的研究的长期目标是了解巨核细胞产生并在活化血小板表面表达的 TFPI 在控制血管内 TF 活性中的作用。我们假设血小板 TFPI 位于最佳位置并集中，以下调生长的血凝块内的 TF 活性。因此，它可以防止血栓形成，从而完全堵塞血管并产生严重的、可能致命的疾病。该假设基于以下几点：1) 血液中的循环 TF 是血栓形成和生长的主要贡献者； 2）TFPI是TF唯一的生理抑制剂； 3) 血小板是凝块形成的主要细胞成分； 4) 肌动蛋白和 TFPI 在活化的血小板内共定位； 5) 缺乏血小板 TFPI 的小鼠的肝脏和大脑中存在大量纤维蛋白沉积，而血小板 TFPI 小鼠中则不存在这种情况。这里提出的实验将确定 1) 静止血小板内 TFPI 的细胞内位置； 2) TFPI转移至活化血小板表面的生化机制； 3) TFPI 缺乏体内小鼠模型中血小板 TFPI 的生理功能。该提案是为期 5 年的职业发展计划的一部分。职业发展计划包括血液学、小鼠病理学和胚胎发生学科的额外培训。与威斯康星州血液中心血液研究所 (BRI) 和威斯康星医学院的基础科学家的持续互动将提供 1) 接触到在血液学、凝血和病理学领域具有专业知识的经验丰富的研究人员，2) 小鼠模型的制作和评估，3) 使用体外和体内系统来研究凝血，以及 4) 通过赞助的访问讲座系列接触国际和国家认可的科学家 由血液研究所提供。随着 Maroney 博士转变为独立资助的研究者，这些机会将为他提供额外的支持和指导。 相关性（参见说明）：该提案与公共健康相关，因为它研究了血小板 TFPI 在下调血小板凝块形成活性中所起的作用。对这些机制的研究将加深我们对血小板如何形成凝块以防止严重出血，同时控制凝块生长以防止可能导致中风或心脏病发作或其他潜在致命疾病的血管闭塞的理解。 （摘要完）