Regulation of Protein C Pathways

蛋白 C 通路的调节

基本信息

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
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/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

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.

活化的蛋白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体生物学。在多种临床前动物损伤模型中，药理学APC提供了好处。 APC不仅具有抗凝活性，而且还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的受体（PAR）。 APC引起的细胞信号传导有助于组织稳态和宿主防御系统。有益APC引发的偏置信号传导通过PAR1和PAR3的特定切割，也可以通过APC结合到内皮上的TIE2触发细胞。尽管最近有见解，但有关蛋白质 - 蛋白质相互作用（PPI）的知识存在很大的差距 APC及其细胞受体。 AIM 1研究将使用28个重组APC突变体的库来提供有关APC受体特异性的数据库，这些数据将使APC突变体的工程受体特异性选择性，例如，具有高选择性PAR1特异性或PAR3特异性信号的APC突变体功能。这种受体选择性的APC突变体将是破译哪些受体的有用试剂在体外或体内动物中细胞的关键作用，它们可能导致新型APC突变体的翻译。一 APC的主要抗炎机制是其最近发现的抑制NLRP3炎性体的能力激活。有主要需要了解APC如何抑制炎性体激活，并针对2个研究将提供高新颖的新知识。当APC相对于凝血酶生成过量产生时，出现出血的风险增加。这可能发生在血友病中或在使用直接口腔中抗凝剂（DOAC）。 AIM 3研究将提供有关鼠出血和关节损害的新知识与相对过度APC相关的血友病模型，将确定各种策略是否可以减少关节损伤是由于血友病关节出血引起的。拟议的研究将提供新颖的机械洞察力和新的APC变体可能有助于与APC途径相关的翻译。