A NOVEL REGULATORY ROLE OF PROTEIN S IN BLOOD COAGULATION

蛋白质在凝血中的新调节作用

基本信息

批准号：
9109029
负责人：
Rinku Majumder
金额：
$ 36.5万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9109029
关键词：
Acceleration Activated Partial Thromboplastin Time measurement Active Sites Amino Acids Anisotropy Antibodies Anticoagulants Anticoagulation Binding Binding Proteins Binding Sites Biological Assay Birth Blood Coagulation Disorders Blood Platelets Blood Vessels Blood coagulation Cardiovascular system Catalytic Domain Cells Chimera organism Coagulation Process Data Deep Vein Thrombosis Defect Development Disease Down-Regulation EGF gene Equilibrium Event F8 gene Factor IX Factor IXa Factor VIIa Factor Xa Feedback Fibrin Future Generations Goals Health Hemophilia A Hemophilia B Hemorrhage Hemostatic Agents Hemostatic function Heparin Heparin Binding Heterozygote Host Defense Mechanism Human In Vitro Infant Infusion procedures Injury Knowledge Label Life Light Link Mass Spectrum Analysis Measurement Measures Mediating Membrane Modeling Morphologic artifacts Mus Mutate Mutation Newborn Infant Patients Phase Phospholipids Physiological Plasma Plasma Proteins Protein S Protein S Deficiency Prothrombin Pulmonary Embolism Purpura Fulminans Recombinants Regulation Reporting Risk Risk Factors Role Saphenous Vein Serine Site Specificity TFPI Testing Thrombin Thrombophilia Thrombosis Thrombus Variant Venous Thrombosis Vesicle Vitamin K Work activated Protein C base cancer procoagulant citrate carrier cofactor design fluorescence imaging fluorophore in vivo inhibitor/antagonist mouse model neutralizing antibody novel novel therapeutics prevent proband protein function research study response time use

项目摘要

DESCRIPTION (provided by applicant): A Novel Role of Protein S in Blood Coagulation Protein S (PS) is an important anticoagulant, deficiencies of which are one of several known risk factors for thrombophilia and increased risk of blood clots such as Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). In severe cases of PS deficiency, soon after birth infants develop a life-threatening blood clotting disorder called purpura fulminans. However, despite 30 years of study of this important anticoagulant, the exact function of PS is still unknown. Protein S was initially characterized as a cofactor of activated protein C (APC), but PS confers only a modest increase in APC activity. Plasma assays in the absence of APC suggested other important, APC-independent roles of PS. Some reports suggest that PS inhibits prothrombin activation to thrombin, but the validity of those reports has been questioned because of artifacts due to PS multimerization. In 2006, it was shown that PS acts as a cofactor of tissue factor pathway inhibitor (TFPI) in the initiation of coagulation. Our recent work has shown that PS inhibits factor IX (FIXa); importantly, we used conditions, e.g., high concentrations of phospholipid vesicles that avoid artifacts from PS multimers. Our goal is to mechanistically define both the physiologically relevant function of PS and the specificity of PS inhibition of FIXa. We will use a multifaceted approach to identify the regulatory role of PS. Our proposal involves detailed in vitro, ex vivo and in vivo studies to establish that protein S inhibition of FXa is specific and physiologically important. This proposal consists of two aims: 1) Determine the contact regions between FIX and PS and 2) establish the physiological significance and specificity of protein S inhibition of FIX. Successful completion of our proposal will sharply defie a novel regulatory role of PS that operates independently of APC and TFPI. The knowledge we acquire of the mechanism of this novel regulatory function will enable future development of new therapeutics designed to target the contact point between FIX and PS. Also, inhibitors of PS activity will form the basis of an adjunct therapy for hemophilia, and, by inhibiting hyper- functional FIX, PS could be used in the treatment of X-linked thrombophilia.

描述（由申请人提供）：蛋白质在血液凝结蛋白S（PS）中的新作用是重要的抗凝剂，缺乏症，其中是血栓形成的几种已知危险因素之一，以及增加血液凝块的风险，例如深静脉血栓形成（DVT）和肺栓塞（PE）。在严重的PS缺乏症的情况下，出生后不久，婴儿患有威胁生命的血液凝结障碍，称为紫米粉。然而，尽管研究了30年的这种重要抗凝剂，但PS的确切功能仍然未知。蛋白质最初被表征为活化蛋白C（APC）的辅助因子，但PS仅赋予APC活性的适度增加。在没有APC的情况下，血浆测定表明PS的其他重要，无关的作用。一些报告表明，PS抑制凝血酶蛋白激活凝血酶，但是由于PS多聚化引起的伪影，这些报告的有效性受到质疑。在2006年，PS在凝结开始时充当组织因子途径抑制剂（TFPI）的辅助因子。我们最近的工作表明，PS抑制因子IX（FIXA）；重要的是，我们使用的是避免PS多聚体伪影的高浓度的磷脂囊泡。我们的目标是机械地定义PS的生理相关功能和PS抑制FIXA的特异性。我们将使用多方面的方法来识别PS的调节作用。我们的建议涉及体外详细的体内和体内研究，以确定FXA的蛋白质抑制是特异性的，并且在生理上很重要。该提案包括两个目的：1）确定固定与PS之间的接触区域以及2）确定蛋白质抑制固定的生理意义和特异性。成功完成我们的建议将大大挑战PS的新型监管作用，该作用独立于APC和TFPI。我们获得了这种新型调节功能机制的知识将使未来的新疗法发展旨在针对固定和PS之间的接触点。同样，PS活性的抑制剂将构成血友病辅助疗法的基础，并且通过抑制功能性固定，PS可以用于治疗X连锁的血小板状态。