权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

活化蛋白C （Activated protein C， APC）是一种天然存在的血浆丝氨酸蛋白酶，已被应用于临床