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Regulation of Inflammation by the Fibrinolytic System

纤溶系统对炎症的调节

基本信息

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
项目类别：
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

项目摘要

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、血栓和血管紊乱