Integrative Multi-Omic Discovery of Proximal Mechanisms Driving Age-Dependent Neurodegeneration

阿尔茨海默病是最常见的神经退行性疾病，临床特点是 由细胞外淀粉样斑块和神经元内形成的认知功能障碍和病理 聚集的tau沉积到神经纤维缠结中。尽管罕见的形式的疾病是由 常染色体显性基因的高度穿透性突变，致病形式较常见的 对疾病的了解还不完全。深入了解损耗的基本驱动机制 衰老过程中神经元完整性的研究将为专注于识别 阿尔茨海默病及相关疾病中神经退行性变的调节途径。因此，要提供一个 我们将全面了解高等真核生物大脑退化的驱动机制 果蝇正向遗传学力量的优势，以不偏不倚的方式概述机制 在衰老过程中控制神经元功能的保存。然后，将我们的发现与人类疾病联系起来 我们将直接使用系统生物学方法，将eQTL分析和rna衍生的网络整合在一起。 来自独特且高质量的激光捕获患者颞叶神经元的数据测序 患有阿尔茨海默氏症的患者和仔细匹配年龄和性别的对照组患者没有神经系统疾病。 我们将通过进行整合的代谢组学和 阿尔茨海默病相关果蝇模型的磷酸蛋白质组学分析 一种转基因动物。由此产生的网络，包括以前未发现或隐藏的节点，将 在具有良好特征的tau模型中测试它们与果蝇神经退行性变的因果关系 和A？神经毒性。因此，我们的研究将在基因组规模上发现新的驱动机制 并将提供最有可能导致细胞死亡的机制的普查 阿尔茨海默氏症及相关疾病。然后，我们发现的基因和途径可以在 适当的哺乳动物模型中的机械细节。

Alzheimer's disease is the most common neurodegenerative disorder and is characterized clinically by cognitive dysfunction and pathologically by the formation of extracellular amyloid plaques and intraneuronal deposition of aggregated tau into neurofibrillary tangles. Although rare forms of the disorder are caused by highly penetrant mutations in autosomal dominant genes, the pathogenesis of more common forms of the disease remains incompletely understood. A thorough understanding of the basic mechanisms driving loss of neuronal integrity during aging would provide a crucial underpinning for efforts focused on identifying the pathways mediating neurodegeneration in Alzheimer's disease and related disorders. Thus, to provide a comprehensive knowledge of mechanisms driving brain degeneration in higher eukaryotes we will take advantage of the power of forward genetics in Drosophila to outline, in an unbiased fashion, mechanisms controlling preservation of neuronal function during aging. Then, to relate our findings to human disease directly we will integrate, using a systems biology approach, networks derived from eQTL analysis and RNA sequencing data from a unique and high-quality resource of laser captured temporal neurons from patients with Alzheimer's disease and carefully age- and sex-matched control patients without neurological disease. We will further discover pathways relevant to disease by performing an integrated metabolomics and phosphoproteomic analysis in Drosophila models relevant to Alzheimer's disease, namely human tau and Aß transgenic animals. The resulting networks, including previously undiscovered, or hidden, nodes will be tested for their causal relationship to neurodegeneration in Drosophila in well-characterized models of tau and Aß neurotoxicity. Our studies will thus discover on a genome scale novel mechanisms driving neurodegeneration and will provide a census of those mechanisms most likely to underlie cell death in Alzheimer's disease and related disorders. The genes and pathways we discover can then be examined in mechanistic detail in the appropriate mammalian models.