Protein S Regulates Blood Coagulation by Inhibiting Factor IXa

Protein S 通过抑制 IXa 因子调节凝血

基本信息

批准号：
10616732
负责人：
Rinku Majumder
金额：
$ 54.01万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-05 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616732
关键词：
Acute Affinity Amino Acids Antibodies Anticoagulants Binding Binding Proteins Binding Sites Biochemical Biological Assay Blood Platelets Blood Vessels Blood coagulation Calorimetry Chimera organism Coagulation Process Deep Vein Thrombosis Development Docking EGF gene Electrostatics Factor IXa Fibrin Fluorescence Anisotropy Functional disorder Funding Goals Hemorrhage Hemostatic function Heparin Binding In Vitro Individual Infusion procedures Knowledge Label Laminin Life Maintenance Measures Mediating Modeling Molecular Molecular Conformation Mus Mutate Mutation Neonatal Thrombocytopenia Pathology Plasma Plasma Proteins Property Protease Domain Protein C Inhibitor Protein Region Protein S Protein S Deficiency Proteins Pulmonary Embolism Purpura Fulminans Saphenous Vein Site Stroke TFPI Tertiary Protein Structure Testing Thrombin Thrombosis Titrations United States National Institutes of Health Up-Regulation Venous Thrombosis activated Protein C cofactor experimental study fluorescence imaging in silico in vivo inhibitor laminin S macromolecule mimetics mutant novel polypeptide protein function response restoration thrombotic

项目摘要

Protein S (PS), a plasma anticoagulant, is vital for the maintenance of hemostasis. Deficiencies or abnormalities in PS can lead to thrombotic conditions such as pulmonary embolism, deep vein thrombosis, and acute small blood vessel coagulation. PS is a non- enzymatic cofactor for Activated Protein C and for Tissue Factor Pathway Inhibitor. Recently, we discovered that PS inhibits procoagulant FIXa. This significant finding likely explains the thrombotic pathology associated with PS deficiency. Thus, we seek to derive a complete understanding of the interaction between FIXa and PS and to establish the explicit importance of the PS-FIXa interaction, exclusive of PS interactions with APC and TFPI. Identification of the biochemical details of PS-FIXa interaction will enable development a small derivative of PS that could treat individuals who have excess FIXa activity (and excess blood clotting) and PS deficiencies or abnormalities. We have pinpointed the PS binding site to FIXa’s heparin-binding site and identified HBE residues necessary for PS-FIXa binding. We have established that the Gla and EGF domains of FIXa contribute to the stability of the interaction with PS, and we discovered that the isolated Laminin G1+2 domains of PS are effective inhibitors of FIXa. For this project, we will use the following in vivo and in vitro approaches to achieve a thorough understanding of the interaction of PS with FIXa: (1) Confirm PS domains required for FIXa inhibition, (2) Identify PS residues required for FIXa inhibition, and (3) Define the in vivo interaction of FIXa with PS LG domains and single-site LG domain mutants. The molecular and biochemical knowledge obtained from this study will provide the basis for creation of a PS- derived FIXa-inhibiting molecule for the treatment of thrombotic conditions caused by PS deficiency or upregulation of FIXa.

蛋白 S (PS) 是一种血浆抗凝剂，对于维持止血至关重要。 PS 缺乏或异常可导致血栓性疾病，例如肺栓塞、深静脉血栓和急性小血管凝固是PS的一种。最近，活性蛋白 C 和组织因子途径抑制剂的酶辅因子。我们发现 PS 会抑制促凝血 FIXa，这一重要发现可能解释了这一现象。因此，我们寻求得出完整的 PS 缺乏相关的血栓病理学。了解 FIXa 和 PS 之间的相互作用并确定明确的重要性 PS-FIXa 相互作用，不包括 PS 与 APC 和 TFPI 的相互作用识别。 PS-FIXa 相互作用的生化细节将有助于开发 PS 的小型衍生物，可以治疗 FIXa 活性过度（和凝血过度）和 PS 的个体缺陷或异常。我们已经精确定位了 PS 结合位点与 FIXa 的肝素结合位点，并鉴定了 HBE 我们已经确定了 PS-FIXa 结合所需的 Gla 和 EGF 结构域。 FIXa 有助于与 PS 相互作用的稳定性，我们发现孤立的 PS 的层粘连蛋白 G1+2 结构域是 FIXa 的有效抑制剂。对于这个项目，我们将使用以下体内和体外方法来实现透彻理解 PS 与 FIXa 的交互： (1) 确认所需的 PS 域 FIXa 抑制，(2) 鉴定 FIXa 抑制所需的 PS 残基，以及 (3) 定义体内 FIXa 与 PS LG 结构域和单位点 LG 结构域突变体的相互作用。从这项研究中获得的生化知识将为创建PS-提供基础衍生的 FIXa 抑制分子用于治疗 PS 引起的血栓性疾病 FIXa 缺乏或上调。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protein S antibody as an adjunct therapy for hemophilia B.

Protein S 抗体作为 B 型血友病的辅助治疗。

DOI：
发表时间：
2024-01-23
期刊：
影响因子：
7.5
作者：
Wilson, Hope P;Pierre, Aliyah;Paysse, Ashley L;Kumar, Narender;Cooley, Brian C;Rudra, Pratyadipta;Dorsey, Adrianne W;Polania;Chatterjee, Sabyasachi;Janbain, Maissaa;Velez, Maria C;Majumder, Rinku
通讯作者：
Majumder, Rinku