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CD14 and TLRs in Abeta-Induced Microglial Signaling

Abeta 诱导的小胶质细胞信号转导中的 CD14 和 TLR

基本信息

批准号：
7477636
负责人：
ERIN G REED
金额：
$ 2.57万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7477636
关键词：
Acids Acute-Phase Proteins Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Animal Model Apoptotic Binding Blocking Antibodies Brain CD14 Antigen CD14 gene CD36 gene CD47 Antigen Cell Surface Receptors Cell surface Cells Complex Deposition Development Disease Disruption Elements Enzyme-Linked Immunosorbent Assay Event Excision Fluorescence Resonance Energy Transfer Functional disorder Glycosylphosphatidylinositols Goals Immune Immune response Immunoprecipitation Individual Inflammation Inflammatory Inflammatory Response Ligands Link Mediating Microbe Microglia Mus Myeloid Cells Natural Immunity Nitrogen Oxygen Pathology Pathway interactions Patients Pattern recognition receptor Peptides Peptidoglycan Phagocytosis Induction Phenotype Play Polymerase Chain Reaction Process Production Protein Tyrosine Kinase Proteins RNAi vector Reactive Oxygen Species Research Proposals Role SR-B proteins Senile Plaques Signal Pathway Signal Transduction Signaling Protein Stimulus Surface TLR2 gene Time Toxic effect Transducers Western Blotting Work base brain cell cytokine design interest link protein macrophage member monocyte mouse model neurotoxic neutrophil novel therapeutics pathogen protein function receptor response scavenger receptor toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): This research proposal is designed to elucidate the mechanisms by which microglia recognize fibrillar beta amyloid (fAbeta) to induce a pro-inflammatory response. This is critical as inflammation has been shown to be intimately involved in the disease pathology of Alzheimer's disease (AD). Interactions of microglia with Ab plaques results in pro-inflammatory signaling cascades and the secretion of neurotoxic secretory products. Previous studies have demonstrated a multi-component receptor complex on the surface of microglia that that mediates the binding of fAb and subsequent activation of intracellular signaling pathways leading to a pro-inflammatory response and an induction of phagocytosis. Moreover, CD14, a protein found on the surface of monocytes and neutrophils that serves as a microbe-detecting receptor to activates immune cells to eliminate pathogens, has been implicated in binding fAb. We hypothesize that CD14 acts as a member of the fAb cell surface receptor complex to bind fAbeta and elicit a pro-inflammatory response. This proposal seeks to determine whether CD14 is required for fAb-induced signaling to intracellular effectors, and whether it associates with the receptor components to do so. It also seeks to identify the signaling cascades downstream of CD14 that produce an inflammatory response. To achieve these goals, she will use a combination of approaches, including function blocking antibodies and RNAi vectors to inhibit protein function, immunoprecipitation and FRET to detect association of fAb receptor complex molecules, Western blot analysis, real-time PCR, and ELISA to detect expression levels of signaling proteins, inflammatory molecules, and Ab peptides, and mice deficient in CD14, TLR4, TLR2, and MyD88, as well as those that model AD to examine the importance of CD14 in microglial activation by fAb and plaque development in a mouse model of AD. This application proposes to better understand the ways in which the immune cells of the brain work to trigger an immune response to the fibrillar Abeta deposits that form in the Alzheimer's disease brain. It will inform development of new therapeutic approaches and a better understanding these processes.

描述（由申请人提供）：本研究计划旨在阐明小胶质细胞识别纤维状β淀粉样蛋白（fAbeta）以诱导促炎反应的机制。这一点至关重要，因为炎症已被证明与阿尔茨海默病 (AD) 的疾病病理学密切相关。小胶质细胞与抗体斑块的相互作用导致促炎信号级联反应和神经毒性分泌产物的分泌。先前的研究表明，小胶质细胞表面存在多组分受体复合物，可介导 fAb 的结合以及随后激活细胞内信号通路，从而导致促炎反应和诱导吞噬作用。此外，CD14 是一种在单核细胞和中性粒细胞表面发现的蛋白质，可作为微生物检测受体，激活免疫细胞消除病原体，与 fAb 的结合有关。我们假设 CD14 作为 fAb 细胞表面受体复合物的成员，结合 fAbeta 并引发促炎反应。该提案旨在确定 fAb 诱导的细胞内效应器信号传导是否需要 CD14，以及它是否与受体成分相关联。它还试图识别 CD14 下游产生炎症反应的信号级联。为了实现这些目标，她将结合使用多种方法，包括功能阻断抗体和RNAi载体来抑制蛋白质功能，免疫沉淀和FRET来检测fAb受体复合物分子的关联，蛋白质印迹分析，实时PCR和ELISA来检测信号蛋白、炎症分子和Ab肽的表达水平，以及CD14、TLR4缺陷的小鼠， TLR2 和 MyD88 以及 AD 模型，以检查 CD14 在 AD 小鼠模型中 fAb 激活小胶质细胞和斑块发育中的重要性。该应用旨在更好地了解大脑免疫细胞如何触发对阿尔茨海默病大脑中形成的纤维状 Abeta 沉积物的免疫反应。它将为新治疗方法的开发和更好地理解这些过程提供信息。