Structure-function of cytoprotective coagulation proteases and their receptors

细胞保护性凝血蛋白酶及其受体的结构-功能

• 批准号: 8585871
• 负责人: Laurent Olivier Mosnier
• 金额: $ 46.43万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8585871
• 关键词: Affect; Antibodies; Apoptosis; Area; Award; Basic Science; Binding; Biochemical; Biological Availability; Blood Platelets; Blood Vessels; Cells; Cellular biology; Cessation of life; Coagulation Process; Complex; Data; Defect; Development; Diagnosis; Diagnostic; Disease; Endotoxins; Engineering; Environment; Factor Xa; Goals; Heparin; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Knowledge; Lead; Life; Mediating; Membrane; Methods; Molecular; Mus; Myocardial Infarction; National Heart, Lung, and Blood Institute; Pathogenesis; Pathway interactions; Peptide Hydrolases; Predisposition; Property; Protein C; Proteolysis; Publishing; Recombinants; Research Personnel; Risk; Role; Sepsis; Signal Transduction; Site; Solutions; Specificity; Stroke; Structure; Structure-Activity Relationship; Testing; Therapeutic; Thrombin; Thrombocytopenia; Thrombomodulin; Thrombosis; Translational Research; Translations; Variant; abstracting; activated Protein C; activated protein C receptor; advanced disease; clinically relevant; cofactor; improved; insight; mortality; novel; novel therapeutics; receptor; success; unpublished works

Project Summary/Abstract This application seeks to improve basic understanding of molecular mechanisms that mediate cytoprotective actions of coagulation proteases on cells. Available therapeutic solutions for vascular, thrombotic, and inflammatory diseases are limited and mortality rates remain unacceptably high. Beneficial effects of activated protein C (APC) on cells contrast with proinflammatory effects of other coagulation proteases (e.g. thrombin and factor Xa) on cells and initiated novel perspectives on the intricate complex networks of receptor-mediated cross talk in cells. Improving therapeutic success requires a more thorough understanding of the molecular mechanisms involved. This proposal is centered on the endothelial protein C receptor (EPCR), a key cytoprotective receptor. The long-term objectives of this application are to contribute to diagnostic and therapeutic progress for vascular, thrombotic, and inflammatory diseases by advancing knowledge through both basic and translational research. The goal of this application is to gain novel insights into the molecular mechanisms of cytoprotective actions mediated by EPCR. The major focus of this application is on structure- function relationships for EPCR that underlie EPCR's cofactor role in the transduction of clinically relevant APC-mediated cytoprotective effects and on translation of this information into improved therapeutic strategies for thrombotic inflammatory diseases. Novel hypotheses will be tested using biochemical and cellular biology methods. The specific aims are: 1) To generate engineered EPCR variants with unique properties that will enhance its ability to mediate cytoprotective effects, 2) To characterize the structure-function determinants for EPCR-dependent PAR-1 activation that are responsible for APC-mediated cytoprotective effects on cells, and 3) To define the thrombotic complications associated with "off-target" Heparin-Induced Thrombocytopenia (HIT) antibodies against PF4-EPCR and PF4-thrombomodulin (TM) complexes. Succesfull completion of the proposed studies will increase our knowledge and understanding of vascular, thrombotic, and inflammatory diseases and may provide a platform for the development of novel therapeutic strategies for a variety of disorders in which thrombosis, apoptosis and inflammation contribute to pathogenesis.

项目概要/摘要 该应用旨在提高对介导细胞保护作用的分子机制的基本理解 凝血蛋白酶对细胞的作用。针对血管、血栓和疾病的可用治疗解决方案 炎症性疾病有限，死亡率仍然高得令人无法接受。激活的有益效果 蛋白 C (APC) 对细胞的促炎作用与其他凝血蛋白酶（例如凝血酶）的促炎作用形成对比 和因子 Xa）对细胞的影响，并为受体介导的复杂网络提出了新的视角 细胞内的串扰。提高治疗成功率需要更透彻地了解分子机制 涉及的机制。该提案以内皮蛋白 C 受体 (EPCR) 为中心，这是一个关键的 细胞保护受体。该应用程序的长期目标是促进诊断和 通过增进知识来促进血管、血栓和炎症疾病的治疗进展 基础研究和转化研究。该应用程序的目标是获得对分子的新见解 EPCR 介导的细胞保护作用机制。该应用程序的主要重点是结构 - EPCR 的功能关系是 EPCR 辅助因子在临床相关转导中作用的基础 APC 介导的细胞保护作用以及将此信息转化为改进的治疗策略 用于血栓性炎症性疾病。新假设将使用生化和细胞生物学进行测试 方法。具体目标是： 1) 生成具有独特特性的工程化 EPCR 变体， 增强其介导细胞保护作用的能力，2）表征其结构功能决定因素 EPCR 依赖性 PAR-1 激活负责 APC 介导的细胞保护作用，以及 3) 定义与“脱靶”肝素诱导的血小板减少症相关的血栓并发症 针对 PF4-EPCR 和 PF4-血栓调节蛋白 (TM) 复合物的 (HIT) 抗体。圆满完成了 拟议的研究将增加我们对血管、血栓和炎症的认识和理解 疾病，并可能为开发针对多种疾病的新治疗策略提供平台 血栓形成、细胞凋亡和炎症参与发病机制的疾病。