ROLE OF GLIA IN NEURONAL DEGENERATION

描述(由申请人提供)：该计划的长期目标是阐明胶质细胞(星形胶质细胞和小胶质细胞)的慢性激活如何与神经元退化有关。我们正在检验以下假设：慢性胶质细胞激活及其对关键蛋白和信号通路的异常调节，以及随之而来的正常神经胶质细胞相互作用的失调，促进了神经细胞的死亡。对神经胶质细胞激活反应的深入了解将使我们能够采用新的方法来调节影响神经退行性疾病进展的神经胶质细胞反应，同时维持正常大脑功能所必需的重要的有益神经胶质细胞反应。我们的重点是关键蛋白质和通路，这些蛋白质和通路与阿尔茨海默病(AD)的病理终点有记载的关系。在人类神经退行性疾病或神经退行性疾病的动物模型中，它们被发现存在异常调控。我们将确定激活的胶质细胞中蛋白质和通路的调节机制，胶质蛋白表达与神经元功能的关系，以及配体调节剂的发现。Van Eldik的项目将通过定义神经胶质细胞因子对神经元死亡的贡献，并使用化学基因组学方法来发现神经元死亡和死亡激酶的小分子调节器，来研究选定的神经胶质神经炎性反应和神经细胞死亡之间的联系。Binder的项目将专注于星形胶质细胞中异常tau的作用及其与细胞骨架完整性和在体外接受炎症反应的能力以及在神经退行性疾病中的关系。LaDu的项目将确定AP如何诱导星形胶质细胞的激活和星形细胞载脂蛋白E的增加，载脂蛋白E受体LRP和LDLR在这些过程中的作用，以及载脂蛋白E的抗炎活性的程度和机制。Vassar项目将测试这一假说，即在AD炎症期间，围绕淀粉样斑块周围的激活星形胶质细胞通过APP的BACE1裂解而加剧斑块发展。设立了两个核心，以提供赠款行政和管理服务(核心A：统计核心)和提供组织学服务(核心B：组织化学核心)。这些项目将利用各种实验模型(原代胶质细胞和神经元的细胞培养模型；阿尔茨海默病和相关神经退行性疾病的新型转基因和敲除小鼠模型；以及人类尸检组织)和学科(合成化学、蛋白质生物化学、细胞和分子生物学、生理学和神经病理学)。研究人员与互补专业人员之间的合作和协同作用为解决有关激活的胶质细胞和神经胶质细胞-神经元相互作用在神经退行性变中的作用的基本问题提供了一种基础广泛但有重点的方法。

DESCRIPTION (provided by applicant): The long-term goal of this Program is to elucidate how chronic activation of glia (astrocytes and microglia) is linked to neuronal degeneration. We are testing the following hypothesis: Chronic glial activation, with its aberrant regulation of key proteins and signaling pathways, and the consequent dysregulation of normal glialneuronal interactions, promotes neuronal cell death. An increased understanding of glial activation responses will allow new approaches to modulate glial responses that influence neurodegenerative disease progression, while maintaining the important beneficial glial responses necessary for normal brain function. Our focus is on key proteins and pathways that have a documented relationship to end points of Alzheimer's disease (AD) pathology. They have been found to be abnormally regulated in human neurodegenerative disease or in animal models of neurodegenerative disease. W e will determine mechanisms of regulation of the proteins and pathways in activated glia, the relationship between glial protein expression and neuronal function, and the discovery of ligand modulators. Project by Van Eldik will examine the link between selected glial neuroinflammatory responses and neuronal cell death by defining glial cytokine contributions to neuronal death, and using chemical genomics approaches to discover small molecule modulators of neuronal death and death kinases. Project by Binder will focus on the role of abnormal tau in astrocytes and its relationship to their cytoskeletal integrity and ability to undergo the inflammatory response in vitro and in neurodegenerative disease. Project by LaDu will determine how AP induces activation of astrocytes and increases in astrocytic apoE, the role of the apoE receptors LRP and LDLR in these processes, and the extent and mechanism of apoE's anti-inflammatory activity. Project Vassar will test the hypothesis that activated astrocytes surrounding amyloid plaques exacerbate plaque development through BACE1 cleavage of APP to generate Ap during AD inflammation. Two cores have been established to provide services in grant administration and management (Core A: Statistical Core) and to perform histological services (Core B: Histochemistry Core). The projects will utilize a variety of experimental models (cell culture models of primary glia and neurons; novel transgenic and knockout mouse models of AD and related neurodegenerative diseases; and human autopsy tissue) and disciplines (synthetic chemistry, protein biochemistry, cell and molecular biology, physiology and neuropathology). The cooperative and synergistic interactions among investigators with complementary expertises provide a broad-based, yet focused, approach to addressing fundamental questions about the role of activated glia and glial-neuronal interactions in neurodegeneration.