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：
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/10693590
关键词：
Address Adult Alteplase Alternative Splicing Alzheimer&apos s Disease Anti-Inflammatory Agents Apolipoprotein E Astrocytes Attenuated Automobile Driving Binding Brain Breeding Cell surface Cells Clinical Colitis Data Disease Disease Progression Elements Fibrinolysis Functional disorder Funding Gene Deletion Gene Expression Genes Genetic Polymorphism Goals Grant Human Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interferon Type II Knockout Mice LDL-Receptor Related Protein 1 Ligands Lipopolysaccharides Lipoprotein Receptor Lipoproteins MAPT gene Macrophage Mediating Membrane Membrane Microdomains Metalloproteases Microglia Mus Mutate N-Methyl-D-Aspartate Receptors N-Methylaspartate NGFR Protein Natural Immunity Nerve Degeneration Neurofibrillary Tangles Neurons Oligodendroglia Pathogenesis Pathologic Pathway interactions Peptide Hydrolases Peripheral Phosphorylation Physiology Plasminogen Activator Play Post-Translational Protein Processing PrP Probability Proteins Receptor Signaling Regulation Role Signal Pathway Signal Transduction Sodium Dextran Sulfate System TLR2 gene TLR4 gene TLR7 gene Tauopathies Testing Toll-like receptors Transgenic Mice United States National Institutes of Health Work alpha 2-Glucoproteins central sensitization exosome extracellular extracellular vesicles glial activation in vivo inhibitor injured knockout gene monocyte mouse model mutant neuroinflammation novel pain processing parent grant promoter receptor response tau aggregation tau function tau interaction

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.

项目概要/摘要低密度脂蛋白受体相关蛋白 1 (LRP1) 具有内吞和细胞信号传导受体的功能为纤溶蛋白酶、组织型纤溶酶原激活剂（tPA）。 tPA 与巨噬细胞中的 LRP1 结合产生抗炎反应，其中多个 Toll 样受体的活性减弱。这反应需要 LRP1 辅助受体，包括 NMDA 受体，这是必不可少的。因为LRP1有众多结构和功能多样的配体，了解不同的配体是否存在非常重要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疾病在中枢神经系统中积累，是神经退行性疾病的主要驱动因素在阿尔茨海默病（AD）中观察到的病理生理学。使用培养的巨噬细胞，我们已经证明 TAU 引起的反应与 tPA 引起的反应不同；事实上，TAU 的功能是依赖 LRP1 的亲炎症因子。神经炎症在 AD 中非常重要，我们假设 TAU 的相互作用大脑中小胶质细胞 LRP1 是小胶质细胞激活、神经炎症和 AD 促性状的主要驱动因素侵略。从机制上讲，我们有证据表明 TAU 激活从细胞中释放 LRP1 的途径表面，将抗炎膜锚定受体转化为高度促炎的可溶性受体衍生品（摆脱LRP1）。此项对家长补助金 R01 HL136395 的补充的主要目标是测试我们的假设论文认为，母基金中正在研究的受体系统被 CNS 中的 TAU 征服，以驱动神经元 AD 中的炎症。提出了两个具体目标。在具体目标 1 中，我们将描述以下相互作用的特征：在培养的小胶质细胞中使用 TAU 与 LRP1，并测试这种相互作用刺激 LRP1 脱落的假设，它激活小胶质细胞并促进炎症。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，我们有必要直接检验这个假设在小胶质细胞中。 TAU 对 LRP1 脱落、小胶质细胞生理学、细胞信号传导和炎症的影响将考虑中介表达。小胶质细胞将从成年条件性基因敲除小鼠中分离出来确认LRP1的作用并测试辅助受体是否参与其中。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学的影响表达人 TAU 的 P301S 突变体。这些小鼠自发形成 TAU 聚集体最终致命的神经炎症在疾病的发病机制中发挥着核心作用。中和这些小鼠的小胶质细胞中 LRP1 的表达将通过与 Lrp1 缺失的小鼠进行繁殖来实现有条件地受到小胶质细胞中活跃的启动子系统的控制。这些研究代表了重要的 R01 HL136395 的扩展具有产生独立的 NIH 资助的巨大潜力，重点关注 AD 神经炎症的全新途径。