PAR SIGNALING AND PROTECTIVE PATHWAYS IN INFLAMMATION AND SEPSIS

炎症和脓毒症中的 PAR 信号传导和保护途径

基本信息

批准号：
7929579
负责人：
WOLFRAM RUF
金额：
$ 67.07万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929579
关键词：
Address Anticoagulants Blood Coagulation Factor Blood Vessels Cells Cleaved cell Coagulants Coagulation Process Complex Couples Coupling Data Dendritic Cell Pathway Dendritic Cells Disease Endothelial Cells Equilibrium Evaluation Extravasation F2R gene Foundations Functional disorder Generations Genetic Goals Grant Immigration Immune Immune system In Vitro Inflammation Inflammatory Inflammatory Response Intervention Knowledge Lipids Lymph Lymphatic System Mediating Morbidity - disease rate Outcome PAR-1 Receptor Pathway interactions Peptide Hydrolases Phenotype Play Positioning Attribute Protein C Proteinase-Activated Receptors Reagent Receptor Activation Receptor Signaling Regulation Research Research Proposals Role Sepsis Sepsis Syndrome Signal Pathway Signal Transduction Specificity Sphingosine-1-Phosphate Receptor Staging Syndrome System Target Populations Testing Therapeutic Therapeutic Intervention Thrombin Transgenic Mice Vascular Endothelium Vascular Permeabilities activated Protein C cell type improved in vivo innate immune function mouse model novel therapeutics receptor research study sphingosine 1-phosphate therapy outcome vascular endothelial dysfunction vascular inflammation

项目摘要

The intrinsic signaling aspects of the coagulation cascade have emerged as major contributors and regulators of systemic inflammation and sepsis. Our experiments uncovered an unexpected thrombin-protease activated receptor (PAR) 1 signaling pathway on dendritic cells (DCs) that is responsible for exacerbated systemic inflammatory response syndromes leading to sepsis lethality. Thrombin-activated PAR1 uniquely couples to sphingosine 1 phosphate (S1P) receptor 3 (S1P3) to promote DC-dependent inflammation and to induce endothelial dysfunction and vascular leakage. Paradoxically, PAR1 signaling by endogenous or therapeutically administered activated protein C (aPC) is sepsis protective. Our data indicate that therapeutic action of aPC targets both DC-dependent inflammation and vascular leakage, excluding that the “PAR1 paradox” can simply be reduced to cell type specific signaling effects. We propose to test the overall hypothesis that coupling of PAR1 to S1P receptor subtypes and regulatory co-receptors are the key determinants for the observed protease signaling specificity of PAR activation in vivo. The experiments in the upcoming two years will advance these concepts by focusing on the role of PAR1 signaling in DCs and endothelial cells. Aim 1 is to define the specific cell populations that are the target for thrombin and aPC signaling to regulate innate immune function in severe sepsis. These experiments advance our understanding of the innate immune cells that are controlled by the intrinsic signaling of the coagulation cascade and lay the foundation for testing new concepts of pharmacological modulation of the pro-inflammatory PAR1-S1P3 signaling pathway of DCs. In Aim 2, we use genetic and pharmacological perturbations of the intravascular coagulant balance to further characterize the dual role of PAR1 as a barrier disruptive and barrier protective receptor in sepsis. These experiments expand our knowledge of how co-receptors of PAR1 signaling contribute to the regulation of vascular barrier function and set the stage for further testing of new therapeutic strategies that improve vascular dysfunction in inflammatory disorders and sepsis. 3.

凝血级联反应的固有信号传导方面已成为全身炎症和败血症的主要贡献者和调节剂。我们的实验发现了树突状细胞（DC）上出现意外的凝血酶激活受体（PAR）1信号通路，该途径导致加剧的全身性炎症反应综合征，导致败血症致死性。凝血酶激活的PAR1独特的夫妻伴有1磷酸1磷酸（S1P）受体3（S1P3）矛盾，内源性或治疗施用的活化蛋白C（APC）的PAR1信号受到败血症的保护。我们的数据表明，APC的治疗作用靶向DC依赖性注射和血管泄漏，不包括“ PAR1悖论”可以简单地减少为细胞类型的特定信号效应。我们建议测试总体假设，即PAR1与S1P受体亚型和调节共受体的耦合是观察到的体内PAR激活的蛋白酶信号传导特异性的关键决定剂。在接下来的两年中的实验将通过关注PAR1信号在DC和内皮细胞中的作用来推进这些概念。目的1是定义特定的细胞群，这是凝血酶和APC信号传导的靶标，以调节严重败血症的先天免疫功能。这些实验提高了我们对由凝血级联反应的固有信号传导控制的先天免疫小球的理解，并为测试DC的促炎PAR1-S13信号通路的药理调制的新概念奠定了基础。在AIM 2中，我们使用血管内凝结平衡的遗传和药物扰动进一步表征PAR1作为败血症中屏障破坏性和屏障保护因子的双重作用。这些实验扩展了我们对PAR1信号传导的共受体的了解，如何促进血管屏障功能的调节，并为进一步测试新的治疗策略奠定了基础，从而改善炎症性疾病和脓毒症中血管功能障碍的新治疗策略。 3。