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: 8050509
• 负责人: Laurent Olivier Mosnier
• 金额: $ 47.38万
• 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/8050509
• 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; activated Protein C; activated protein C receptor; advanced disease; clinically relevant; cofactor; improved; insight; mortality; novel; novel therapeutics; receptor; receptor expression; success; unpublished works

DESCRIPTION (provided by applicant): 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 pro-inflammatory 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. Successful 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. PUBLIC HEALTH RELEVANCE: Vascular, thrombotic, and inflammatory diseases, such as sepsis, heart attack or stroke, will affect most of us at some point in life, with a profound impact on the quality and duration of life thereafter. Available therapeutic solutions are limited and mortality rates remain unacceptably high. Guided by the encouraging beneficial effects of recombinant activated protein C in sepsis and stroke, the proposed studies will identify novel molecular mechanisms and create engineered molecular variants for translational research and potential safer and more effective therapeutic applications.

描述（由申请人提供）：本申请旨在提高对介导凝固蛋白酶对细胞的细胞保护作用的分子机制的基本理解。可用于血管、血栓和炎性疾病的治疗解决方案是有限的，并且死亡率仍然高得不可接受。活化蛋白C（APC）对细胞的有益作用与其他凝血蛋白酶（如凝血酶和Xa因子）对细胞的促炎作用形成对比，并引发了对细胞中受体介导的串扰的错综复杂的复杂网络的新观点。提高治疗成功率需要更深入地了解所涉及的分子机制。该建议集中在内皮蛋白C受体（EPCR），一种关键的细胞保护受体。本申请的长期目标是通过基础和转化研究促进知识，为血管、血栓和炎症疾病的诊断和治疗进展做出贡献。本申请的目的是获得新的见解的分子机制EPCR介导的细胞保护作用。本申请的主要焦点是EPCR的结构-功能关系，其是EPCR的辅因子在临床相关APC介导的细胞保护作用的转导中的作用的基础，以及将该信息翻译成血栓性炎性疾病的改进的治疗策略。新的假设将使用生物化学和细胞生物学方法进行测试。具体目标是：1）产生具有独特性质的工程化EPCR变体，其将增强其介导细胞保护作用的能力，2）表征负责APC介导的细胞保护作用的EPCR依赖性PAR-1活化的结构-功能决定因素，和3）确定与针对PF 4-EPCR和PF 4-EPCR的“脱靶”肝素诱导的血小板减少症（HIT）抗体相关的血栓形成并发症。血栓调节蛋白（TM）复合物。成功完成拟议的研究将增加我们对血管、血栓形成和炎症性疾病的知识和理解，并可能为开发各种疾病的新治疗策略提供平台，其中血栓形成、细胞凋亡和炎症有助于发病机制。 公共卫生相关性：血管性、血栓性和炎症性疾病，如败血症、心脏病发作或中风，将在生命的某个阶段影响我们大多数人，并对此后的生活质量和持续时间产生深远影响。现有的治疗办法有限，死亡率仍然高得令人无法接受。在重组活化蛋白C在脓毒症和中风中令人鼓舞的有益作用的指导下，拟议的研究将确定新的分子机制，并为转化研究和潜在的更安全，更有效的治疗应用创造工程分子变体。