Structure and Function of Protein C

蛋白C的结构和功能

基本信息

批准号：
8386992
负责人：
JOHN H GRIFFIN
金额：
$ 66.92万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-12-18 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8386992
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Activated Protein C Resistance Adaptor Signaling Protein Address Adult Affinity Alkaline Phosphatase Amino Acids Anti-Inflammatory Agents Anti-inflammatory Anticoagulants Antithrombins Apoptotic Area Basic Science Binding Biological Biological Assay Blood Cells Blood Vessels Cell Surface Receptors Cells Cessation of life Clinic Clinical Clinical Research Coagulation Process Cytoprotection Data Diagnostic Disabled Persons Dissection Engineering Factor Va Failure Funding Future Gene Expression Alteration Glycogen Synthase Kinases Goals Individual Inherited Knowledge Laboratories Lead Ligation Link Low Density Lipoprotein Receptor Measurable Mediating Molecular Mutagenesis Mutation Neonatal Thrombocytopenia PAR-1 Receptor Papio Pathway interactions Patients Physiological Plasma Proteins Protein C Protein C Deficiency Protein Deficiency Protein S Proteins Publishing Purpura Fulminans Reaction Recombinants Reporter Research Research Project Grants Risk Role Sepsis Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Site-Directed Mutagenesis Sphingosine-1-Phosphate Receptor Structure Surface Surface Plasmon Resonance TFPI Therapeutic Translating Translational Research U937 Cells United States National Institutes of Health VLDL receptor Variant Venous Thrombosis Work activated Protein C activated protein C receptor apolipoprotein E receptor 2 base chymotrypsin citrate carrier clinically relevant cofactor inhibitor/antagonist insight loss of function mortality mutant novel prevent public health relevance receptor receptor binding research study screening sphingosine 1-phosphate src-Family Kinases success tool unpublished works

项目摘要

DESCRIPTION (provided by applicant): Previous basic research on Protein C, a naturally occurring plasma protein, has been translated into diagnostic and therapeutic tools now used in the clinic. Activated protein C (APC) exerts two major and distinct activities, (1) anticoagulant activity and (2) initiation of cell signaling that activates multiple cytoprotective activities. The cytoprotective actions include anti-apoptotic and anti-inflammatory activities, favorable alterations of gene expression, and stabilization of endothelial barriers. Whereas the antithrombotic actions of APC have long been appreciated, only very recently has the physiologic and pharmacologic importance of APC's direct effects on cells become apparent. According to a recently established, incomplete paradigm, APC's cell signaling involves binding of APC by endothelial protein C receptor (EPCR) combined with protease activated receptor-1 (PAR1) proteolytic activation. Our preliminary data identify an additional novel cell signaling pathway for APC, namely a "reelin-like" signaling pathway involving ligation of apolipoprotein E Receptor 2 (apoER2) that initiates signaling via the intracellular adaptor protein, disabled-1 (Dab1), and Src-family kinases (Src and Fyn) with subsequent downstream actions via the phosphatidylinositol-3-kinase (PI3K)-Akt survival pathway. We need to understand mechanisms for APC's cell signaling reactions and its multiple cytoprotective effects. The three Specific Aims of this hypothesis-driven project are: 1) to define the structural basis for binding of APC to apoER2; 2) to prepare and characterize new APC variants with novel mutations that selectively alter APC's targeting of PAR1 and apoER2; and 3) to clarify molecular mechanisms and the roles for each of the various APC receptors responsible each of APC's direct cytoprotective effects on cells. This proposal will address multiple key questions about APC-receptor interactions. The answers from this basic research project may have direct clinical relevance with substantial impact for both basic and clinical research and with obvious clinical implications.

描述（由申请人提供）：先前对蛋白C（一种天然存在的血浆蛋白）的基础研究已转化为目前用于临床的诊断和治疗工具。活化蛋白 C (APC) 发挥两种主要且不同的活性，(1) 抗凝活性和 (2) 启动细胞信号传导，激活多种细胞保护活性。细胞保护作用包括抗凋亡和抗炎活性、基因表达的有利改变以及内皮屏障的稳定。尽管 APC 的抗血栓作用早已受到重视，但直到最近，APC 对细胞的直接作用的生理学和药理学重要性才变得明显。根据最近建立的不完整范式，APC 的细胞信号转导涉及 APC 与内皮蛋白 C 受体 (EPCR) 的结合以及蛋白酶激活受体 1 (PAR1) 的蛋白水解激活。我们的初步数据确定了 APC 的另一种新型细胞信号传导途径，即涉及载脂蛋白 E 受体 2 (apoER2) 连接的“reelin 样”信号传导途径，该途径通过细胞内接头蛋白、disabled-1 (Dab1) 和 Src 启动信号传导-家族激酶（Src 和 Fyn）通过磷脂酰肌醇-3-激酶 (PI3K)-Akt 生存途径发挥后续下游作用。我们需要了解 APC 细胞信号反应的机制及其多种细胞保护作用。这个假设驱动项目的三个具体目标是： 1) 定义 APC 与 apoER2 结合的结构基础； 2) 制备和表征具有新突变的新 APC 变体，这些新突变选择性地改变 APC 对 PAR1 和 apoER2 的靶向； 3) 阐明负责 APC 对细胞的直接细胞保护作用的各种 APC 受体的分子机制和作用。该提案将解决有关 APC 受体相互作用的多个关键问题。该基础研究项目的答案可能具有直接的临床相关性，对基础研究和临床研究产生重大影响，并具有明显的临床意义。