The Biochemistry and Physiology of Platelet TFPI

血小板 TFPI 的生物化学和生理学

基本信息

批准号：
8470690
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
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470690
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 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

项目摘要

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）是启动血液凝结的组织因子/因子VILA（TF/VLLA）催化复合物的主要抑制剂。因此，TFPI是一种有效的抗凝蛋白。脉管系统内的TF量增加了诸如动脉粥样硬化和癌症的疾病，从而产生血管内血栓形成，可能导致常见和严重疾病，例如心脏病发作，中风和肺栓塞。我们提出的研究的长期目标是了解巨核细胞产生的TFPI的作用，并在激活血小板的表面表达在控制血管内TF活性中。我们假设血小板TFPI是最佳位置和浓缩的，以便在生长的血凝块中下调TF活性。因此，它防止了完全阻塞血管并产生严重的，可能致命的疾病的血液凝块的形成。该假设基于以下基础：1）血液中循环TF是凝块形成和生长的主要原因； 2）TFPI是TF的唯一生理抑制剂； 3）血小板是凝块形成的主要细胞成分； 4）肌动蛋白和TFPI在活化的血小板中共定位； 5）缺乏血小板TFPI的小鼠在其肝脏和大脑中具有大量的纤维蛋白沉积，而血小板TFPI的小鼠中不存在。这里提出的实验将确定1）TFPI在静止血小板中的细胞内位置； 2）将TFPI转移到活化血小板表面的生化机制； 3）在TFPI缺乏的体内小鼠模型中，血小板TFPI的生理功能。该建议是跨越5年的职业发展计划的一部分。职业发展计划包括有关血液学，小鼠病理学和胚胎发生学科的额外培训。 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由血液研究所。随着Maroney博士向独立资助的调查员的过渡，这些机会将提供额外的支持和指导。相关性（参见建筑）：该提案与公共卫生有关，因为它调查了血小板TFPI在下调血小板活动中的作用。对这些机制的研究将增强我们对血小板如何形成凝块以防止严重出血的理解，同时控制凝块生长，以防止血管阻塞，从而导致中风或心脏病发作或其他潜在的致命疾病。（抽象的结尾）