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

驱动年龄依赖性神经变性的近端机制的综合多组学发现

基本信息

批准号：
9413689
负责人：
MEL B FEANY
金额：
$ 476.08万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9413689
关键词：
Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Automobile Driving Binding Proteins Biological Models Biological Preservation Brain Caenorhabditis elegans Cell Death Cell physiology Censuses Chromosomes, Human, Pair 17 Clinical Complex Data Death Rate Deposition Development Disease Dominant Genes Drosophila genus Eukaryota FTD with parkinsonism Gene Expression Genes Genetic Genetic Transcription Genetic study Human Human Genetics Impaired cognition Influentials Knowledge Lasers Link Mediating Messenger RNA Microtubules Modeling Modification Molecular Molecular Profiling Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Pathogenesis Pathologic Pathway interactions Patients Peptides Play Prevalence Protein Precursors RNA Splicing Regulator Genes Reporting Resources Risk Factors Role Seminal Senile Plaques Signal Transduction System Systems Biology Tauopathies Testing Transgenic Animals Variant Work age related age related neurodegeneration design disorder control extracellular familial Alzheimer disease forward genetics gene discovery genetic analysis genome wide association study genome-wide genomic data hippocampal pyramidal neuron human disease metabolomics nervous system disorder neuron loss neurotoxicity non-genetic novel phosphoproteomics progressive neurodegeneration risk variant sex tau Proteins tau aggregation transcriptome sequencing

项目摘要

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.

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。