Genetic modifiers of motor neuron degeneration

运动神经元变性的遗传修饰

基本信息

批准号：
8010032
负责人：
Randal Scot Tibbetts
金额：
$ 22.28万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-19 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8010032
关键词：
Abbreviations Accounting Adult Affect Age Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Cell Cycle Cells Cessation of life Complement Cytoplasmic Inclusion DNA-Binding Proteins Disease Disease Pathway Dose Drosophila genus Drosophila melanogaster Etiology Event Exhibits Eye Familial Amyotrophic Lateral Sclerosis Family Caregiver Frontotemporal Lobar Degenerations Functional disorder Gene Dosage Gene Expression Genes Genetic Genetic Screening Goals Grant Head Human Huntington Disease Huntington protein Inherited Lead Link Longevity Mediating Microarray Analysis Modeling Motor Neuron Disease Motor Neurons Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Nuclear RNA Paralysed Pathogenesis Pathway interactions Patients Pattern Phosphorus Principal Investigator Prions Process Proteins RNA RNA-Binding Proteins Resolution Rodent Model Screening procedure Solubility Staging System Tars Testing Transgenic Organisms Transmission Electron Microscopy Ubiquitin Up-Regulation age related ataxia telangiectasia mutated protein base fly insight interest motor neuron degeneration neurotoxicity notch protein novel novel therapeutics overexpression presenilin programs protein TDP-43 protein aggregate public health relevance superoxide dismutase 1 tool ubiquilin

项目摘要

DESCRIPTION (provided by applicant): The principle objective of this application is to discover novel disease pathways in a Drosophila melanogaster model of amyotrophic lateral sclerosis (ALS). Recently, dominant mutations in the RNA binding protein TDP-43 (43 kDa TAR DNA-binding protein) have been causally linked to ALS. In addition, ubiquitin-positive, insoluble aggregates of TDP-43 are frequently observed in degenerating motor neurons of ALS patients, suggesting that deregulation of TDP-43 through mutation or epigenetically is a precipitating event in this disease. We have generated a fruit-fly model of TDP-43 proteinopathy in which the expression of human TDP-43 in the motor neurons of flies leads to age- dependent paralysis and death. In this model, TDP-43 retains a nuclear expression pattern, suggesting that TDP-43 need not aggregate to cause motor neuron dysfunction. Based on these findings we hypothesized that TDP-43-dependent changes in nuclear gene expression are responsible for neurodegeneration. Consistent with this idea, gene expression analysis of TDP-43 transgenic flies identified deregulation of cellular pathways with plausible links to neurodegeneration. The goal of the present proposal is to use the Drosophila TDP-43 model to gain new insights into TDP-43-dependent neurodegeneration. The grant encompasses two specific aims. In Aim 1 we will perform microarray and RIP-Chip studies to identify TDP-43 RNA targets in motor neurons. In Aim 2 we will perform screens for genetic modifiers of TDP-43-dependent neurodegeneration, using both candidate and unbiased approaches. The combined studies should illuminate mechanisms of neurodegeneration in ALS and related proteinopathies that may lead to new therapeutic options. PUBLIC HEALTH RELEVANCE: ALS is an intractable condition that exerts severe tolls on affected patients, their families, and caregivers. Comprehensive approaches aimed at identifying the operative mechanisms in this disease are urgently needed. We believe that the fruit fly model of ALS to be explored in this proposal will provide important clues regarding ALS pathogenesis that may lead to new therapies.

描述（由申请人提供）：本申请的主要目的是在肌萎缩侧索硬化症（ALS）的黑腹果蝇模型中发现新的疾病途径。最近，RNA 结合蛋白 TDP-43（43 kDa TAR DNA 结合蛋白）的显性突变与 ALS 存在因果关系。此外，在 ALS 患者退化的运动神经元中经常观察到泛素阳性、不溶性的 TDP-43 聚集体，这表明通过突变或表观遗传导致的 TDP-43 失调是该疾病的一个促发事件。我们建立了 TDP-43 蛋白病的果蝇模型，其中人 TDP-43 在果蝇运动神经元中的表达导致年龄依赖性麻痹和死亡。在此模型中，TDP-43 保留了核表达模式，表明 TDP-43 无需聚集即可引起运动神经元功能障碍。基于这些发现，我们假设 TDP-43 依赖性核基因表达变化是神经变性的原因。与这一想法一致，TDP-43 转基因果蝇的基因表达分析发现细胞通路的失调与神经变性可能存在联系。本提案的目标是使用果蝇 TDP-43 模型来获得对 TDP-43 依赖性神经变性的新见解。该赠款包括两个具体目标。在目标 1 中，我们将进行微阵列和 RIP 芯片研究，以确定运动神经元中的 TDP-43 RNA 靶标。在目标 2 中，我们将使用候选方法和无偏方法对 TDP-43 依赖性神经变性的遗传修饰物进行筛选。联合研究应阐明 ALS 神经退行性变和相关蛋白质病的机制，这可能会带来新的治疗选择。公共卫生相关性：ALS 是一种棘手的疾病，给受影响的患者、其家人和护理人员造成严重损失。迫切需要旨在确定这种疾病的运作机制的综合方法。我们相信，本提案中要探索的 ALS 果蝇模型将为 ALS 发病机制提供重要线索，从而可能带来新的治疗方法。