Regulation of Inflammation by the Fibrinolytic System

纤溶系统对炎症的调节

基本信息

  • 批准号:
    10358335
  • 负责人:
  • 金额:
    $ 39.5万
  • 依托单位:
  • 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

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 本研究项目的重点是纤溶系统及其在调节天然免疫中的活性。我们有 显示组织型纤溶酶原激活物(tPA)作为促炎反应的拮抗剂起作用 在巨噬细胞和小鼠体内由Toll样受体(TLR)触发。从机制上讲,tPA的活性 由包括N-甲基-D-天冬氨酸受体(NMDA-R)和LDL受体的受体系统介导。 相关蛋白1(LRP 1)。虽然酶活性tPA在先天免疫中的功能是由 丝氨酸蛋白酶抑制剂、PAI 1和通过纤溶酶产生无酶活性tPA(EI-tPA)对这些调节具有抗性 途径。EI-tPA未能抑制模式识别受体(PRR)介导的促炎反应 然而,在多种PRR共同发挥功能的疾病小鼠模型中, 在右旋糖酐硫酸钠(DSS)结肠炎模型和K/BxN血清转移性关节炎模型中,EI-tPA是有效的 作为候选治疗药物。在本申请中,为了继续获得支持,我们建议进行研究,以阐明 tPA及其受体在调节炎症中的作用,并确定产生新型抗炎症的潜力。 基于tPA结构的炎性药物。提出了四个具体目标。具体目标1: 通过基因工程确定调节先天免疫所需的tPA中的元件。小说 EI-tPA的重组衍生物将被开发和测试,目的是优化tPA用作 候选的体内抗炎治疗剂。具体目标2的重点是了解反通胀- 由NMDA-R下游的tPA激活的炎性细胞信号传导途径。新的初步结果表明, 一种新型系统,涉及Src家族激酶对Trk受体的反式激活,这在以前的文献中未描述 巨噬细胞和其他炎性细胞。具体目标2中拟议的研究不仅有助于 我们对tPA信号传导的一般理解,也可以确定抗炎症的新的细胞内靶点, 基于我们对tPA激活的细胞信号传导的分析的炎性药物开发。在《特定目标3》中, 小鼠在我们的实验室产生的动物,其中巨噬细胞和其他细胞,其中LysM 启动子有活性的不表达NMDA-R。这将使我们能够明确地测试假设,即反- EI-tPA的体内炎性活性,例如中和LPS毒性,需要NMDA-R, 巨噬细胞和/或嗜中性粒细胞是EI-tPA靶细胞。在具体目标4中,我们将研究tPA的活性, 其抗炎受体NMDA-R和LRP 1在DSS结肠炎模型中的作用。单细胞转录组 提出了谱分析研究以无偏倚的方式鉴定EI-tPA体内靶向的结肠细胞, 鉴定EI-tPA在该模型系统中引起有利反应的新途径。统称 本文提出的研究应进一步了解止血和免疫之间的接口 并进一步努力挖掘纤溶系统用于新型抗炎药物的开发。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

STEVEN L. GONIAS其他文献

STEVEN L. GONIAS的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('STEVEN L. GONIAS', 18)}}的其他基金

A novel role for Reelin therapeutics in inflammatory bowel disease
Reelin 疗法在炎症性肠病中的新作用
  • 批准号:
    10079713
  • 财政年份:
    2020
  • 资助金额:
    $ 39.5万
  • 项目类别:
Regulation of Inflammation by the Fibrinolytic System
纤溶系统对炎症的调节
  • 批准号:
    9913997
  • 财政年份:
    2017
  • 资助金额:
    $ 39.5万
  • 项目类别:
Regulation of Inflammation by the Fibrinolytic System
纤溶系统对炎症的调节
  • 批准号:
    10557130
  • 财政年份:
    2017
  • 资助金额:
    $ 39.5万
  • 项目类别:
Regulation of Inflammation by the Fibrinolytic System
纤溶系统对炎症的调节
  • 批准号:
    9285496
  • 财政年份:
    2017
  • 资助金额:
    $ 39.5万
  • 项目类别:
Regulation of Inflammation by the Fibrinolytic System
纤溶系统对炎症的调节
  • 批准号:
    10693590
  • 财政年份:
    2017
  • 资助金额:
    $ 39.5万
  • 项目类别:
Targeting the Urokinase Receptor in Glioblastoma Multiforme
靶向多形性胶质母细胞瘤中的尿激酶受体
  • 批准号:
    8613477
  • 财政年份:
    2013
  • 资助金额:
    $ 39.5万
  • 项目类别:
Targeting the Urokinase Receptor in Glioblastoma Multiforme
靶向多形性胶质母细胞瘤中的尿激酶受体
  • 批准号:
    8501950
  • 财政年份:
    2013
  • 资助金额:
    $ 39.5万
  • 项目类别:
Targeting the Urokinase Receptor in Glioblastoma Multiforme
靶向多形性胶质母细胞瘤中的尿激酶受体
  • 批准号:
    9023503
  • 财政年份:
    2013
  • 资助金额:
    $ 39.5万
  • 项目类别:
Targeting the Urokinase Receptor in Glioblastoma Multiforme
靶向多形性胶质母细胞瘤中的尿激酶受体
  • 批准号:
    9215655
  • 财政年份:
    2013
  • 资助金额:
    $ 39.5万
  • 项目类别:
Urokinase Receptor-initiated Cell-signaling
尿激酶受体启动的细胞信号传导
  • 批准号:
    7909207
  • 财政年份:
    2009
  • 资助金额:
    $ 39.5万
  • 项目类别:

相似海外基金

Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
  • 批准号:
    2334970
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Standard Grant
NSF-BSF: Towards a Molecular Understanding of Dynamic Active Sites in Advanced Alkaline Water Oxidation Catalysts
NSF-BSF:高级碱性水氧化催化剂动态活性位点的分子理解
  • 批准号:
    2400195
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Standard Grant
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
  • 批准号:
    2334969
  • 财政年份:
    2024
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Standard Grant
Mechanochemical synthesis of nanocarbon and design of active sites for oxygen reducton/evolution reactions
纳米碳的机械化学合成和氧还原/演化反应活性位点的设计
  • 批准号:
    23K04919
  • 财政年份:
    2023
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Creation of porous inorganic frameworks with controlled structure of metal active sites by the building block method.
通过积木法创建具有金属活性位点受控结构的多孔无机框架。
  • 批准号:
    22KJ2957
  • 财政年份:
    2023
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Catalysis of Juxaposed Active Sites Created in Nanospaces and Their Applications
纳米空间中并置活性位点的催化及其应用
  • 批准号:
    23K04494
  • 财政年份:
    2023
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Generation of carbon active sites by modifying the oxygen containing functional groups and structures of carbons for utilizing to various catalytic reactions.
通过修饰碳的含氧官能团和结构来产生碳活性位点,用于各种催化反应。
  • 批准号:
    23K13831
  • 财政年份:
    2023
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
CAREER: CAS: Understanding the Chemistry of Palladium and Silyl Compounds to Design Catalyst Active Sites
职业:CAS:了解钯和甲硅烷基化合物的化学性质以设计催化剂活性位点
  • 批准号:
    2238379
  • 财政年份:
    2023
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Continuing Grant
CAS: Collaborative Research: Tailoring the Distribution of Transient vs. Dynamic Active Sites in Solid-Acid Catalysts and Their Impacts on Chemical Conversions
CAS:合作研究:定制固体酸催化剂中瞬时活性位点与动态活性位点的分布及其对化学转化的影响
  • 批准号:
    2154399
  • 财政年份:
    2022
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Standard Grant
Engineering of Active Sites in Heterogeneous Catalysts for Sustainable Chemical and Fuel Production.
用于可持续化学和燃料生产的多相催化剂活性位点工程。
  • 批准号:
    RGPIN-2019-06633
  • 财政年份:
    2022
  • 资助金额:
    $ 39.5万
  • 项目类别:
    Discovery Grants Program - Individual
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了