Regulation of Protein C Pathways

蛋白 C 通路的调节

• 批准号: 9579234
• 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
• 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/9579234
• 关键词: Abbreviations; Acids; Acute; Animals; Anti-inflammatory; Anticoagulants; Apoptotic; Area; Basic Science; Binding; Blood coagulation; Caspase; Cells; Clinic; Clinical Research; Clinical Trials; Collection; Data; Databases; Diabetes Mellitus; Dimensions; Disease; Endothelial Cells; 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; Integrins; Interleukins; Intervention; Ischemia; Ischemic Stroke; Islets of Langerhans Transplantation; Joints; Kidney; Kidney Transplantation; Knowledge; Lead; Libraries; Link; Lung; 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; Radiation; Reagent; Recombinant Proteins; Recombinants; Recovery; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Risk; Role; Serine Protease; Signal Transduction; Specificity; 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 type; cofactor; design; enzyme activity; gastrointestinal; healing; hexachlorocyclohexane x-factor; improved; in vivo; insight; joint injury; lung injury; man; mortality; mutant; nerve stem cell; novel; pre-clinical; pre-clinical research; preclinical study; protein protein interaction; receptor; regenerative; success; tool; vascular bed

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，已被翻译到临床 作为重组野生型或突变生物制剂。在各种临床前动物损伤模型中， 药理学APC提供益处。APC不仅具有抗凝活性，而且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 有助于组织稳态和宿主防御系统。有益的APC启动的偏置信号传导引起 通过PAR 1和PAR 3的特异性切割，也可以通过APC与内皮细胞上的Tie 2结合来触发。 细胞尽管最近的见解，有一个主要的差距，在知识的蛋白质-蛋白质相互作用（PPI）之间 APC及其细胞受体。目的1研究将使用28个重组APC突变体的文库来提供一种新的表达载体。 关于APC的受体特异性的数据库，其然后将使得能够工程化APC突变体， 受体特异性选择性，例如，具有高度选择性PAR 1特异性或PAR 3特异性信号传导的APC突变体 能力的这种受体选择性APC突变体将是有用的试剂，用于破译哪些受体发挥作用， 在体外细胞或动物体内，它们可能导致新的APC突变体的翻译。一 APC的主要抗炎机制是其最近发现的抑制NLRP 3炎性体的能力 activation.主要需要了解APC如何抑制炎性小体激活，Aim 2研究 将提供高度新颖的新知识。当APC相对于凝血酶产生过量产生时， 增加了出血的风险。这可能会发生在血友病或直接口服期间 抗凝剂（DOAC）。目的3研究将提供关于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 新的APC变体，这可能有助于与APC途径相关的翻译。