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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：
9310284
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 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9310284
关键词：
Acceleration Activated Partial Thromboplastin Time measurement Active Sites Amino Acids Anisotropy Antibodies Anticoagulants Anticoagulation Binding 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 Hemophilia A Hemophilia B Hemorrhage Hemostatic Agents Hemostatic function Heparin Heparin Binding Heterozygote Host Defense Mechanism Human In Vitro Infant Infusion procedures Injectable Injury Knowledge Label Life Light Link Mass Spectrum Analysis Measurement Measures Mediating Membrane Modeling Morphologic artifacts Mus Mutate Mutation Newborn Infant Pathologic Patients Phase Phosphatidylserines Phospholipids Physiological Plasma Plasma Proteins Protein Inhibition Protein S Prothrombin Pulmonary Embolism Purpura Fulminans Recombinants Regulation Reporting Risk Risk Factors Role Saphenous Vein Site Specificity TFPI Testing Thrombin Thrombophilia Thrombosis Thrombus Variant Venous Thrombosis Vesicle Vitamin K Work activated Protein C cancer procoagulant cofactor design experimental study fluorescence imaging fluorophore in vivo inhibitor/antagonist mouse model neutralizing antibody novel novel therapeutics prevent proband protein function public health relevance 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S在血液凝固中的新作用蛋白S（PS）是一种重要的抗凝剂，其缺乏是血栓形成倾向和血栓风险增加（如深静脉血栓形成（DVT）和肺栓塞（PE））的几个已知风险因素之一。在PS缺乏的严重病例中，出生后不久的婴儿会出现一种危及生命的凝血障碍，称为暴发性紫癜。然而，尽管对这种重要的抗凝剂进行了30年的研究，但PS的确切功能仍然未知。蛋白S最初被表征为活化蛋白C（APC）的辅因子，但PS仅赋予APC活性的适度增加。在APC的情况下，血浆分析表明其他重要的，APC独立的PS的作用。一些报告表明，PS抑制凝血酶原活化为凝血酶，但这些报告的有效性受到质疑，因为PS多聚化造成的伪影。2006年，研究表明PS在凝血启动中作为组织因子途径抑制物（TFPI）的辅因子。我们最近的工作表明，PS抑制因子IX（FIXa）;重要的是，我们使用的条件，例如，高浓度的磷脂囊泡，避免了PS多聚体的假象。我们的目标是从机制上定义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确定PS的监管作用。我们的建议包括详细的体外、离体和体内研究，以确定蛋白S抑制FXa是特异性的和生理学上重要的。该建议包括两个目的：1）确定FIX和PS之间的接触区域和2）建立蛋白S抑制FIX的生理意义和特异性。成功完成我们的建议将大大defie一个新的监管作用的PS独立运作的APC和TFPI。我们获得的关于这种新型调节功能机制的知识将使未来能够开发旨在靶向FIX和PS之间接触点的新疗法。此外，PS活性抑制剂将成为血友病辅助治疗的基础，并且通过抑制高功能FIX，PS可用于治疗X连锁血栓形成倾向。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anticoagulant Protein S Targets the Factor IXa Heparin-Binding Exosite to Prevent Thrombosis.

DOI：
10.1161/atvbaha.117.310588
发表时间：
2018-04
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Plautz WE;Sekhar Pilli VS;Cooley BC;Chattopadhyay R;Westmark PR;Getz T;Paul D;Bergmeier W;Sheehan JP;Majumder R
通讯作者：
Majumder R

Protein S: a Multifunctional Anticoagulant.

Protein S：一种多功能抗凝剂。