Regulation of Inflammation by the Fibrinolytic System

纤溶系统对炎症的调节

基本信息

  • 批准号:
    10693590
  • 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

Project Summary/Abstract Low Density Lipoprotein Receptor-related Protein-1 (LRP1) functions as an endocytic and cell-signaling receptor for the fibrinolysis protease, tissue-type plasminogen activator (tPA). Binding of tPA to LRP1 in macrophages generates an anti-inflammatory response in which the activity of multiple Toll-like Receptors is attenuated. This response requires LRP1 co-receptors, including the NMDA Receptor, which is essential. Because LRP1 has numerous structurally and functionally diverse ligands, it is extremely important to understand whether different ligands generate distinct signaling responses. The microtubule-associated protein, TAU, is a recently identified LRP1 ligand which accumulates in the CNS in various forms of neurodegeneration and is a major driver of the pathophysiology observed in Alzheimer's Disease (AD). Using cultured macrophages, we have shown that TAU elicits responses that are distinct from those elicited from tPA; in fact, TAU functions as an LRP1-dependent pro- inflammatory factor. Neuro-inflammation is highly important in AD and we hypothesize that interaction of TAU with microglial LRP1 in the brain is a major driver of microglial activation, neuro-inflammation, and AD pro- gression. Mechanistically, we have evidence that TAU activates pathways that release LRP1 from the cell surface, converting the anti-inflammatory membrane-anchored receptor into a highly pro-inflammatory soluble derivative (shed LRP1). The major goal of this supplement to parent grant R01 HL136395 is to test our hypo- thesis that the receptor system under study in the parent grant is subjugated by TAU in the CNS to drive neuro- inflammation in AD. Two specific aims are proposed. In Specific Aim 1, we will characterize the interaction of TAU with LRP1 in cultured microglia and test the hypothesis that this interaction stimulates LRP1 shedding, which activates microglia and promotes inflammation. Although our previous work suggests that the activities of LRP1 ligands are conserved in macrophages and microglia, it is imperative that we test this hypothesis directly in microglia. The effects of TAU on LRP1 shedding, microglial physiology, cell-signaling, and inflammatory mediator expression will be considered. Microglia will be isolated from adult conditional gene knock-out mice to confirm the role of LRP1 and test whether co-receptors are involved. In Specific Aim 2, we will study the effects of microglial LRP1 on neuro-inflammation and the pathophysiology that develops in transgenic mice that express the P301S mutant of human TAU. These mice develop spontaneous TAU aggregates that are eventually lethal and neuro-inflammation plays a central role in the pathogenesis of disease. Neutralization of LRP1 expression in microglia in these mice will be accomplished by breeding with mice in which Lrp1 is deleted conditionally under the control of promoter systems active in microglia. These studies represent an important extension of R01 HL136395 with significant potential to generate an independent NIH-funded grant focusing on a completely novel pathway for neuro-inflammation in AD.
项目摘要/摘要 低密度脂蛋白受体相关蛋白-1(LRP1)是一种内吞和细胞信号受体 对于纤溶蛋白水解酶、组织型纤溶酶原激活物(TPA)。巨噬细胞中tPA与LRP1的结合 产生一种抗炎反应,其中多种Toll样受体的活性被减弱。这 反应需要LRP1共同受体,包括NMDA受体,这是必不可少的。因为LRP1有 众多结构和功能不同的配体,了解不同的 配体产生不同的信号反应。微管相关蛋白TAU是最近发现的一种 LRP1配体,以各种形式的神经退行性变积聚在中枢神经系统,是 阿尔茨海默病(AD)的病理生理观察。使用培养的巨噬细胞,我们已经证明了TAU 引起不同于tPA的反应;事实上,TAU作为LRP1依赖的PRO- 炎症因子。神经炎症在阿尔茨海默病中非常重要,我们假设TAU的相互作用 大脑中的小胶质细胞LRP1是小胶质细胞激活、神经炎症和AD发病的主要驱动力。 太夸张了。从机制上讲,我们有证据表明TAU激活了从细胞中释放LRP1的途径 表面,将抗炎膜锚定的受体转化为高度促炎的可溶性 导数(脱落LRP1)。家长补助金R01 HL136395的主要目的是测试我们的次要目标- 论文认为,父母赠款中研究的受体系统被中枢神经系统中的TAU抑制,以驱动神经- AD的炎症反应。提出了两个具体目标。在具体目标1中,我们将描述 Tau和LRP1在培养的小胶质细胞中的相互作用,并检验这种相互作用刺激LRP1脱落的假设, 它能激活小胶质细胞,促进炎症。尽管我们之前的工作表明, LRP1配体在巨噬细胞和小胶质细胞中是保守的,我们必须直接检验这一假说。 在小胶质细胞中。TAU对LRP1脱落、小胶质细胞生理、细胞信号转导和炎症的影响 调解人的表达将被考虑。将从成年条件性基因敲除小鼠中分离出小胶质细胞 以确定LRP1的作用,并测试是否有辅助受体参与。在具体目标2中,我们将研究 小胶质细胞LRP1对转基因小鼠神经炎症和病理生理的影响 表达人TAU突变体P301S。这些小鼠产生自发的TAU聚集体,这些聚集体 最终,致命性和神经性炎症在疾病的发病机制中起着核心作用。中和 这些小鼠的小胶质细胞中LRP1的表达将通过与LRP1缺失的小鼠杂交来实现 有条件地受小胶质细胞中活跃的启动子系统的控制。这些研究代表了一项重要的 延长R01 HL136395,有很大潜力产生NIH资助的独立赠款,重点是 阿尔茨海默病神经炎症的全新途径。

项目成果

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STEVEN L. GONIAS其他文献

STEVEN L. GONIAS的其他文献

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{{ 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:
    10358335
  • 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:
    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:
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:

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