Regulation of Inflammation by the Fibrinolytic System

纤溶系统对炎症的调节

• 批准号: 9285496
• 负责人: STEVEN L. GONIAS
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-10 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9285496
• 关键词: Acute; Alteplase; Annexins; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Arthritis; Atherosclerosis; Attention; Attenuated; Binding; Biological Models; CREB1 gene; Cell Surface Receptors; Cell surface; Cells; Chronic; Complement; Complex; Dangerousness; Development; Disseminated Intravascular Coagulation; Endotoxins; Equilibrium; Event; Exposure to; FDA approved; Fc Receptor; Fibrin; Fibrinogen; Fibrinolysis; Gene Expression; Gene Expression Regulation; Goals; Hemostatic function; Immunity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Ischemic Stroke; K/BxN model; LDL-Receptor Related Protein 1; Ligand Binding; Ligands; Lipopolysaccharides; Low-Density Lipoproteins; MicroRNAs; Modeling; Mus; Myeloid Cells; Myocardial Infarction; N-Methyl-D-Aspartate Receptors; National Heart, Lung, and Blood Institute; Natural Immunity; Paper; Pathologic Processes; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Plasminogen; Plasminogen Activator; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Play; Proteins; Receptor Signaling; Recruitment Activity; Regulation; Reporting; Research Project Grants; Role; Sepsis; Serpins; Serum; Signal Pathway; Signal Transduction; Signaling Protein; Specificity; Sterility; Stimulus; System; Systems Biology; TLR4 gene; Testing; Thrombosis; Tissues; Toxic effect; Trauma; Wild Type Mouse; cytokine; drug development; experimental study; gene product; in vivo; inhibitor/antagonist; lipoteichoic acid; low density lipoprotein inhibitor; macrophage; new therapeutic target; novel; protein function; receptor; response; transcriptome

Hemostasis and immunity are highly interrelated systems. Dysregulation of hemostasis, thrombosis, and dis- seminated intravascular coagulation (DIC) are serious complications observed in patients with trauma, sterile tissue injury, systemic inflammation, and sepsis. This research project focuses on a novel pathway by which the major intravascular activator of fibrinolysis, tissue-type Plasminogen Activator (tPA), controls innate im- munity and inflammation. LDL Receptor-related Protein-1 (LRP1) is an endocytic and cell-signaling receptor for tPA. When LRP1 is deleted conditionally in myeloid cells in mice, the inflammatory response to lipopoly- saccharide/endotoxin (LPS) is greatly exacerbated. In LRP1-deficient macrophages, NFκB is activated and expression of pro-inflammatory cytokines is robustly increased. microRNA-155 expression also is increased, which may sustain inflammation, as is expression of the Serpin fibrinolysis inhibitors, plasminogen activator inhibitor-1 (PAI-1) and PAI-2, which contribute to a pro-thrombotic state. In macrophages that express LRP1, different ligands that bind to LRP1 have opposite effects on macrophage phenotype and gene expression, a phenomenon that we hypothesize reflects ligand-specific recruitment of macrophage co-receptors, including N- methyl-D-aspartate Receptor. tPA-binding to LRP1 is anti-inflammatory. Enzymatically-inactive tPA (EI-tPA) blocks the toxicity of LPS in wild-type mice. The anti-inflammatory activity of tPA represents a novel and unanticipated activity of an FDA-approved drug. The major objective of this grant application is to elucidate the activity of tPA in inflammation and a novel pathway by which tPA may counteract development of thrombosis in tissue injury and sepsis. Three specific aims are proposed. In Specific Aim 1, we apply a systems biology approach to elucidate the anti-inflammatory signaling pathway activated by EI-tPA-binding to LRP1 in macro- phages. Specific attention will be dedicated to identifying co-receptors, systems of signaling proteins that func- tion concomitantly to regulate gene expression, and gene products such as SOCS1 and SOCS3, which may determine whether the effects of tPA on inflammation are sustained. In Specific Aim 2, we test the hypothesis that tPA suppresses inflammation in response to multiple stimuli by examining two alternative model systems in mice, lipoteichoic acid challenge and the passive K/BxN serum-transfer arthritis model, in which innate im- munity is activated by Fc receptors and complement factors. In Specific Aim 3, we test the hypothesis that EI- tPA may counteract development of pro-thrombotic states in conditions such as trauma and sepsis by controlling gene expression in macrophages. Proposed experiments in Specific Aim 3 focus on the balance between plasminogen activators and their inhibitors and on cell-surface receptors that promote plasminogen activation by tPA. Overall, this project offers an opportunity to further our understanding of crosstalk between fibrinolysis and cellular systems that control inflammation. The novel pathways under investigation may yield new targets for drug development in chronic inflammation and hemostasis.

止血和免疫是高度相关的系统。止血失调、血栓形成和 弥漫性血管内凝血（DIC）是在创伤、无菌性 组织损伤、全身炎症和败血症。这项研究项目的重点是一种新的途径， 纤维蛋白溶解的主要血管内激活物，组织型纤溶酶原激活物（tPA），控制先天性免疫， 免疫和炎症。低密度脂蛋白受体相关蛋白1（LRP 1）是一种内吞和细胞信号受体 对于tPA。当LRP 1在小鼠骨髓细胞中有条件地缺失时，对脂多糖的炎症反应， 糖/内毒素（LPS）的作用大大加剧。在LRP 1缺陷型巨噬细胞中，NFκB被激活， 促炎细胞因子的表达强烈增加。microRNA-155表达也增加， 其可维持炎症，如丝氨酸蛋白酶抑制剂纤维蛋白溶解抑制剂、纤溶酶原激活剂 抑制剂-1（派-1）和派-2，它们导致血栓形成前状态。在表达LRP 1的巨噬细胞中， 与LRP 1结合的不同配体对巨噬细胞表型和基因表达具有相反的作用， 我们假设这种现象反映了巨噬细胞共受体的配体特异性募集，包括N- 甲基-D-天冬氨酸受体。tPA与LRP 1的结合是抗炎的。无酶活性tPA（EI-tPA） 阻断LPS对野生型小鼠的毒性。tPA的抗炎活性代表了一种新的， FDA批准的药物的意外活性。这项拨款申请的主要目的是阐明 tPA在炎症中的活性和一种新的途径，通过这种途径tPA可以抵消血栓形成的发展， 组织损伤和败血症。提出了三个具体目标。在具体目标1中，我们应用系统生物学 方法阐明巨噬细胞中EI-tPA与LRP 1结合激活的抗炎信号通路， - 是的特别注意将致力于确定共同受体，系统的信号蛋白，功能， 同时调节基因表达，以及基因产物如SOCS 1和SOCS 3， 确定tPA对炎症的影响是否持续。在具体目标2中，我们检验了假设 tPA抑制炎症反应的多种刺激，通过检查两个替代模型系统， 在小鼠中，脂磷壁酸攻击和被动K/BxN血清转移关节炎模型，其中先天性免疫缺陷， 免疫性由Fc受体和补体因子激活。在具体目标3中，我们检验了EI- tPA可以通过以下方式对抗诸如创伤和脓毒症等病症中血栓形成前状态的发展： 控制巨噬细胞中的基因表达。具体目标3中拟议的实验侧重于平衡 在纤溶酶原激活剂及其抑制剂之间以及在促进纤溶酶原的细胞表面受体上 激活tPA。总的来说，这个项目提供了一个机会，以进一步了解串扰之间的 纤维蛋白溶解和控制炎症的细胞系统。正在研究的新途径可能会产生 慢性炎症和止血药物开发的新靶点。