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，其缺乏是导致血栓形成倾向和血栓形成（例如深静脉血栓形成）风险增加的几个已知危险因素之一。 DVT）和肺栓塞（PE）。在 PS 严重缺乏的情况下，婴儿出生后不久就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 最初被定性为活化蛋白 C (APC) 的辅助因子，但 PS 只能适度提高 APC 活性。在没有 APC 的情况下进行的血浆测定表明 PS 具有其他重要的、不依赖于 APC 的作用。一些报告表明 PS 抑制凝血酶原活化为凝血酶，但由于 PS 多聚化造成的伪影，这些报告的有效性受到质疑。 2006年，研究表明PS在凝血启动过程中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，我们使用的条件，例如高浓度的磷脂囊泡，可以避免 PS 多聚体的伪影。我们的目标是从机制上定义 PS 的生理相关功能和 FIXa 的 PS 抑制的特异性。我们将采用多方面的方法来确定PS的监管作用。我们的建议涉及详细的体外、离体和体内研究，以确定 FXa 的 Protein S 抑制是特异性的且具有生理学重要性。该提案有两个目的：1) 确定 FIX 和 PS 之间的接触区域，2) 确定 FIX 的蛋白 S 抑制的生理意义和特异性。我们提案的成功完成将严重挑战 PS 独立于 APC 和 TFPI 运作的新监管角色。我们对这种新型调节功能机制的了解将使未来开发针对 FIX 和 PS 之间接触点的新疗法成为可能。此外，PS活性抑制剂将构成血友病辅助治疗的基础，并且通过抑制功能亢进的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.

抗凝蛋白 S 靶向因子 IXa 肝素结合外位点以预防血栓形成。

DOI：
发表时间：
2018-04
期刊：
影响因子：
0
作者：
Plautz, William E;Sekhar Pilli, Vijaya Satish;Cooley, Brian C;Chattopadhyay, Rima;Westmark, Pamela R;Getz, Todd;Paul, David;Bergmeier, Wolfgang;Sheehan, John P;Majumder, Rinku
通讯作者：
Majumder, Rinku

Hypoxia downregulates protein S expression.

缺氧会下调蛋白 S 的表达。