Regulation of Protein C Pathways

蛋白 C 通路的调节

基本信息

批准号：
9915961
负责人：
JOHN H GRIFFIN
金额：
$ 94.4万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915961
关键词：
Abbreviations Acids Acute Animals Anti-Inflammatory Agents Anticoagulants Apoptotic Area Basic Science Binding Biological Blood coagulation Caspase Cells Clinic Clinical Research Clinical Trials Collection Data Databases Diabetes Mellitus Dimensions Disease Endothelial Cells Endothelium Engineering F2R gene Factor V Factor X Feedback Future Generations Heart Heart Injuries Hemophilia A Hemophilia B Hemorrhage Hemostatic function Homeostasis Host Defense Hyperactive behavior ITGAM gene ITGB2 gene In Vitro Inflammasome Inflammation Inflammatory Injury Injury to Kidney Integrins Interleukins Intervention Ischemia Ischemic Stroke Islets of Langerhans Transplantation Joints Kidney Transplantation Knowledge Lead Libraries Link Lung infections Macrophage-1 Antigen Maintenance Mediating Mission Modeling Molecular Mus Mutation Nervous System Trauma Normal Cell Oral Organ Outcome Pathology Pathway interactions Pharmacology Phenotype Plasma Play Protein C Protein S Proteinase-Activated Receptors Pseudomonas Reagent Recombinant Proteins Recombinants Recovery Regulation Reperfusion Injury Reperfusion Therapy Research Risk Role Serine Protease Signal Transduction Specificity Stroke Structure Surface System Testing Therapeutic Thrombin Thrombomodulin Thrombosis Tissues Translating Translations Variant Whole-Body Irradiation activated Protein C activated protein C receptor apolipoprotein E receptor 2 arthropathies base cell injury cell type cofactor design enzyme activity gastrointestinal healing improved in vivo insight ischemic injury joint injury lung injury man mortality mutant nerve stem cell novel pre-clinical pre-clinical research preclinical study protein protein interaction radiation mitigation receptor regenerative success tool vascular bed

项目摘要

Activated protein C (APC) is a naturally occurring plasma serine protease that has been translated to the clinic as a recombinant wild type or mutant biologic. In a diverse collection of preclinical animal injury models, pharmacologic APC provides benefits. APC not only has anticoagulant activity but also initiates cell signaling via multiple receptors, in particular via several protease activated receptors (PAR). APC-initiated cell signaling contributes to tissue homeostasis and host defense systems. Beneficial APC-initiated biased signaling is caused by specific cleavages of PAR1 and PAR3, and it also can be triggered by APC binding to Tie2 on endothelial cells. Despite recent insights, there is a major gap in knowledge about protein-protein interactions (PPI) between APC and its cellular receptors. Aim 1 studies will use a library of 28 recombinant APC mutants to provide a database regarding APC's receptor specificities which will then enable engineering of APC mutants with receptor-specific selectivity, e.g., an APC mutant with highly selective PAR1-specific or PAR3-specific signaling capabilities. Such receptor-selective APC mutants will be useful reagents for deciphering which receptors play critical roles on cells in vitro or in animals in vivo, and they may lead to translation for novel APC mutants. One major anti-inflammatory mechanism for APC is its recently discovered ability to inhibit NLRP3 inflammasome activation. There a major need for understanding how APC inhibits inflammasome activation, and Aim 2 studies will provide highly novel new knowledge. When APC is generated in excess relative to thrombin generation, increased risk for bleeding arises. This may potentially occur in hemophilia or during use of direct oral anticoagulant (DOAC). Aim 3 studies will provide new knowledge about bleeding and joint damage in murine hemophilia models linked to relatively excessive APC and will determine whether various strategies may reduce joint damage that arises due to bleeding in hemophilic joints. The proposed studies will provide novel mechanistic insights and new APC variants which may aid translation related to the APC pathways.

活化蛋白C (APC) 是一种天然存在的血浆丝氨酸蛋白酶，已转化为临床作为重组野生型或突变型生物制品。在各种临床前动物损伤模型中，药理学 APC 具有益处。 APC不仅具有抗凝活性，还能启动细胞信号传导通过多种受体，特别是通过几种蛋白酶激活受体（PAR）。 APC 启动的细胞信号传导有助于组织稳态和宿主防御系统。引起有益的 APC 发起的偏向信号传导通过 PAR1 和 PAR3 的特异性裂解，也可以通过 APC 与内皮细胞上的 Tie2 结合来触发细胞。尽管最近有了一些见解，但关于蛋白质-蛋白质相互作用 (PPI) 之间的知识仍存在重大差距。 APC 及其细胞受体。目标 1 研究将使用 28 个重组 APC 突变体的文库来提供有关 APC 受体特异性的数据库，然后可以利用该数据库对 APC 突变体进行工程设计受体特异性选择性，例如具有高度选择性 PAR1 特异性或 PAR3 特异性信号传导的 APC 突变体能力。这种受体选择性 APC 突变体将成为破译哪些受体发挥作用的有用试剂对体外细胞或动物体内细胞发挥关键作用，并且它们可能导致新型 APC 突变体的翻译。一 APC 的主要抗炎机制是最近发现的抑制 NLRP3 炎症小体的能力激活。迫切需要了解 APC 如何抑制炎症小体激活，以及 Aim 2 研究将提供高度新颖的新知识。当 APC 生成量相对于凝血酶生成量过多时，出血风险增加。这可能发生在血友病或使用直接口服药物期间抗凝剂（DOAC）。目标 3 研究将提供有关小鼠出血和关节损伤的新知识血友病模型与相对过量的 APC 相关，并将确定各种策略是否可以减少由于血友病关节出血而引起的关节损伤。拟议的研究将提供新的机制见解和新的 APC 变体可能有助于与 APC 途径相关的翻译。