权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of Inflammation by the Fibrinolytic System

纤溶系统对炎症的调节

基本信息

批准号：
10557130
负责人：
STEVEN L. GONIAS
金额：
$ 39.5万
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 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557130
关键词：
Activator Appliances Active Sites Agonist Alteplase Animals Anti-Inflammatory Agents Arthritis Binding Biological Models Bone Marrow Breeding Cell physiology Cells Chemistry Chronic Clinical Colon Complex Data Disease Disease Progression Disease model Dose Elements Engineering Family Fibrinolysis Funding G-Protein-Coupled Receptors Gene Deletion Generations Genetic Engineering Goals Grant Hemostatic function Immunity In Vitro Inflammation Inflammatory Inflammatory Response K/BxN model LDL-Receptor Related Protein 1 Laboratories Lipopolysaccharides Macrophage Macrophage Colony-Stimulating Factor Mediating Modeling Mus N-Methyl-D-Aspartate Receptors NMDA receptor A1 Natural Immunity Pathogenesis Pathology Pathway interactions Pattern recognition receptor Peptide Hydrolases Peritoneal Macrophages Pharmaceutical Preparations Phase Plasmin Plasminogen Plasminogen Activator Plasminogen Activator Inhibitor 1 Process Progress Reports Proteins Publishing Recombinants Regulation Regulatory Pathway Research Project Grants Resistance Serine Serine Protease Serpins Serum Signal Pathway Signal Transduction Structure Symptoms System TLR2 gene TLR4 gene TLR7 gene Testing Therapeutic Tissues Toll-like receptors Toxic effect Transactivation Wild Type Mouse Work antagonist aspartate receptor cell type cytokine dextran sulfate sodium induced colitis drug development drug discovery experimental study gut inflammation improved in vivo mimetics monocyte mouse model neutrophil novel promoter receptor receptor function response src-Family Kinases therapeutic candidate tissue injury transcriptomic profiling

项目摘要

Abstract This research project focuses on the fibrinolysis system and its activity in regulating innate immunity. We have shown that tissue-type plasminogen activator (tPA) functions as an antagonist of pro-inflammatory responses triggered by Toll-like Receptors (TLRs) in macrophages and in vivo in mice. Mechanistically, the activity of tPA is mediated by a receptor system that includes the N-methyl-D-aspartate receptor (NMDA-R) and LDL Receptor- related Protein-1 (LRP1). Although the function of enzymatically-active tPA in innate immunity is regulated by the Serpin, PAI1, and by plasmin generation, enzymatically-inactive tPA (EI-tPA) is resistant to these regulatory pathways. EI-tPA fails to inhibit pro-inflammatory responses mediated by Pattern Recognition Receptors (PRRs) other than TLRs; however, in mouse models of disease in which multiple PRRs function in concert, including the Dextran Sulfate Sodium (DSS) colitis model and the K/BxN serum-transfer arthritis model, EI-tPA is efficacious as a candidate therapeutic. In this application for continued support, we propose studies to elucidate the activity of tPA and its receptors in regulating inflammation and determine the potential to generate novel anti-inflam- matory drugs based on the structure of tPA. Four specific aims are proposed. In Specific Aim 1, the structural elements in tPA required for regulation of innate immunity will be determined by genetic engineering. Novel recombinant derivatives of EI-tPA will be developed and tested with the goal of optimizing tPA for use as a candidate anti-inflammatory therapeutic in vivo. Specific Aim 2 is focused on understanding the anti-inflam- matory cell-signaling pathway activated by tPA downstream of the NMDA-R. New preliminary results implicate a novel system, involving Trk receptor transactivation by Src family kinases, which is previously undescribed in macrophages and other inflammatory cells. The proposed studies in Specific Aim 2 will not only contribute to our understanding of tPA signaling in general but also may identify novel intracellular targets for anti-inflam- matory drug development based on our analysis of tPA-activated cell-signaling. In Specific Aim 3, we will breed mice available in our laboratory to generate animals in which macrophages and other cells in which the LysM promoter is active do not express the NMDA-R. This will allow us to definitively test the hypothesis that the anti- inflammatory activity of EI-tPA in vivo, for example in neutralizing LPS toxicity, requires the NMDA-R and that macrophages and/or neutrophils are EI-tPA target cells. In Specific Aim 4, we will study the activity of tPA and its anti-inflammatory receptors, the NMDA-R and LRP1, in the DSS colitis model. Single-cell transcriptome profiling studies are proposed to identify, in an unbiased manner, colon cells targeted by EI-tPA in vivo and identify novel pathways by which EI-tPA elicits a favorable response in this model system. Collectively, the studies proposed herein should further our understanding of the interface between hemostasis and immunity and further efforts to mine the fibrinolysis system for novel anti-inflammatory drug development.

摘要