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

• 批准号: 7743980
• 负责人: WOLFRAM RUF
• 金额: $ 65.45万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 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/7743980
• 关键词: Address; Age; Attenuated; Blood Vessels; Cause of Death; Cells; Cleaved cell; Coagulants; Coagulation Process; Complex; Couples; Coupling; Data; Dendritic Cell Pathway; Dendritic Cells; Disease; Endothelial Cells; Equilibrium; Extravasation; F2R gene; Foundations; Functional disorder; Funding; Future; Genetic; Genetic Models; Goals; Grant; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Laboratories; Lipids; Morbidity - disease rate; Mus; Mutant Strains Mice; PAR-1 Receptor; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Play; Protein C; Proteinase-Activated Receptors; Receptor Activation; Receptor Signaling; Regulation; Role; Sepsis; Sepsis Syndrome; Signal Pathway; Signal Transduction; Specificity; Sphingosine-1-Phosphate Receptor; Staging; Syndrome; Target Populations; Testing; Therapeutic; Therapeutic Intervention; Thrombin; Vascular Endothelium; activated Protein C; cell type; immune function; improved; in vivo; insight; mouse model; mutant; novel; novel strategies; novel therapeutics; receptor; research study; sphingosine 1-phosphate; vascular endothelial dysfunction; vascular inflammation

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.

凝血级联的内在信号传导方面已成为全身炎症和脓毒症的主要贡献者和调节者。我们的实验发现了树突状细胞 (DC) 上意想不到的凝血酶蛋白酶激活受体 (PAR) 1 信号通路，该通路导致全身炎症反应综合征加剧，导致败血症致死。凝血酶激活的 PAR1 独特地与 1 磷酸鞘氨醇 (S1P) 受体 3 (S1P3) 偶联，促进 DC 依赖性炎症并诱导内皮功能障碍和血管渗漏。矛盾的是，内源性或治疗性施用的活化蛋白 C (aPC) 发出的 PAR1 信号传导具有脓毒症保护作用。我们的数据表明，aPC 的治疗作用针对 DC 依赖性炎症和血管渗漏，排除“PAR1 悖论”可以简单地简化为细胞类型特异性信号传导效应。我们建议测试以下总体假设：PAR1 与 S1P 受体亚型和调节辅助受体的偶联是观察到的体内 PAR 激活的蛋白酶信号传导特异性的关键决定因素。未来两年的实验将通过关注 PAR1 信号在 DC 和内皮细胞中的作用来推进这些概念。目标 1 是确定作为凝血酶和 aPC 信号传导的靶标的特定细胞群，以调节严重脓毒症中的先天免疫功能。这些实验加深了我们对由凝血级联的内在信号控制的先天免疫细胞的理解，并为测试 DC 促炎 PAR1-S1P3 信号通路的药理学调节新概念奠定了基础。在目标 2 中，我们利用血管内凝血平衡的遗传和药理学扰动来进一步表征 PAR1 作为败血症中屏障破坏性和屏障保护性受体的双重作用。这些实验扩展了我们对 PAR1 信号转导共受体如何促进血管屏障功能调节的认识，并为进一步测试改善炎症性疾病和脓毒症血管功能障碍的新治疗策略奠定了基础。 3.