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Genome-wide analysis of tau neurotoxicity

tau 神经毒性的全基因组分析

基本信息

批准号：
8457652
负责人：
MEL B FEANY
金额：
$ 40.51万
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：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8457652
关键词：
Actins Adult Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Precursor Animal Model Animals Asses Behavioral Biochemical Biological Biological Assay Biological Models Cell Culture Techniques Cells Cessation of life Chromosomes, Human, Pair 17 Collection Complement Cytoskeleton DNA Damage Data Deposition Disease Drosophila genome Drosophila genus FTD with parkinsonism Frontotemporal Dementia Functional disorder Gene Expression Genes Genetic Genetic Models Genetic Screening Genetic Variation Genome Human Influentials Investigation Lesion Libraries Link Mediating Modeling Modification Molecular Molecular Analysis Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Parkinsonian Disorders Pathogenesis Pathologic Pathway interactions Patients Phenotype Phosphorus Positioning Attribute Predisposition Progressive Supranuclear Palsy Proteins Publishing RNA Interference RNA Splicing Reporting Retinal Role Sampling Screening Result Screening procedure Senile Plaques Tauopathies Testing Time Tissues Toxic effect Transgenic Mice Transgenic Organisms Validation age related base corticobasal degeneration design early onset extracellular fly genetic analysis genome wide association study genome-wide genome-wide analysis in vivo innovation interest mouse model neurotoxicity progressive neurodegeneration research study tau Proteins tau aggregation tau phosphorylation therapeutic target transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease is the most common neurodegenerative disorder and is characterized pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated tau protein and by the formation of extracellular amyloid plaques. Abnormal deposition of tau into neurofibrillary tangles is also the primary pathologic feature of a group of less common disorders, collectively termed the "tauopathies." To define the molecular mechanisms controlling tau-induced neurodegeneration we and others have modeled tauopathies in the simple and powerful genetic model organism Drosophila. Genetic, biochemical and cell biological experiments in Drosophila have provided important clues regarding the pathogenesis of tauopathies. However, the unbiased forward genetic screens providing the bases for these studies, while valuable, have to date remained incomplete. Here we propose to use newly created and powerful whole- genome transgenic RNAi collections to perform comprehensive genetic analysis of tau neurotoxicity in vivo. We will complement these studies by with a state of the art transcriptomics in human Alzheimer's disease neurons. These studies will for the first time provide a comprehensive analysis of mechanisms controlling tau toxicity to postmitotitc neurons and should identify many new high-value therapeutic targets. Our studies will be particularly important as more and more data emerges from genome wide associated studies showing genetic influences on Alzheimer's disease and related tauopathies, but with little clear evidence as to the mechanism of action of these newly identified gene products in neurodegenerative disease pathogenesis. PUBLIC HEALTH RELEVANCE: The proposed studies will combine the strengths of fruit flies as a fast, cheap model system to identify causal factors in tau neurotoxicity with state-of-the-art molecular analysis of tissue from patients with Alzheimer's disease to outline mechanisms controlling cell dysfunction and death in neurodegeneration. These studies will help us design better therapies for Alzheimer's disease and related neurodegenerative disorders.

描述（由申请人提供）：阿尔茨海默病是最常见的神经变性疾病，其病理特征为异常磷酸化和聚集的tau蛋白的神经元内沉积以及细胞外淀粉样斑块的形成。tau蛋白异常沉积到神经元缠结中也是一组不太常见的疾病的主要病理特征，统称为“tau蛋白病”。“为了定义控制tau诱导的神经变性的分子机制，我们和其他人在简单而强大的遗传模式生物果蝇中模拟了tau蛋白病。果蝇的遗传学、生物化学和细胞生物学实验为tau蛋白病的发病机制提供了重要线索。然而，为这些研究提供基础的无偏正向遗传筛选虽然有价值，但迄今仍不完整。在这里，我们建议使用新创建的和强大的全基因组转基因RNAi集合进行全面的遗传分析的tau神经毒性在体内。我们将通过人类阿尔茨海默病神经元中最先进的转录组学来补充这些研究。这些研究将首次全面分析控制tau蛋白对核分裂后神经元毒性的机制，并确定许多新的高价值治疗靶点。我们的研究将特别重要，因为越来越多的数据来自全基因组相关研究，显示对阿尔茨海默病和相关tau蛋白病的遗传影响，但几乎没有明确的证据表明这些新发现的基因产物在神经退行性疾病发病机制中的作用机制。公共卫生相关性：拟议的研究将联合收割机的优势，果蝇作为一个快速，廉价的模型系统，以确定因果因素的tau神经毒性与国家的最先进的对阿尔茨海默病患者的组织进行分子分析，以概述控制神经变性中细胞功能障碍和死亡的机制。这些研究将帮助我们设计更好的治疗阿尔茨海默病和相关的神经退行性疾病的方法。