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：
8113164
负责人：
Randal Scot Tibbetts
金额：
$ 18.19万
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/8113164
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 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性侧面硬化症（ALS）的果蝇模型中发现新型疾病途径。最近，RNA结合蛋白TDP-43（43 kDa TAR DNA结合蛋白）的显性突变已与ALS有因果关系。此外，在ALS患者的退化运动神经元中，经常观察到TDP-43的泛素阳性，不溶性骨料，这表明通过突变或表观遗传上对TDP-43进行管制是该病中的降水事件。我们已经生成了TDP-43蛋白质病的果阳性模型，其中人类TDP-43在蝇的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，这表明TDP-43不需要骨料引起运动神经元功能障碍。基于这些发现，我们假设核基因表达的TDP-43依赖性变化是神经变性的原因。与这个想法一致，TDP-43转基因蝇的基因表达分析鉴定出与神经变性的合理联系的细胞途径的放松管制。本建议的目的是使用果蝇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的目标。在AIM 1中，我们将进行微阵列和RIP-CHIP研究，以鉴定运动神经元中的TDP-43 RNA靶标。在AIM 2中，我们将使用候选和无偏见的方法对TDP-43依赖性神经变性的遗传修饰剂进行筛选。合并的研究应阐明可能导致新的治疗选择的ALS和相关蛋白质病中神经退行性的机制。公共卫生相关性：ALS是一种棘手的疾病，对受影响的患者，其家人和护理人员造成严重的伤害。迫切需要采用旨在识别该疾病中手术机制的综合方法。我们认为，该提案中要探索的ALS的果蝇模型将为可能导致新疗法的ALS发病机理提供重要的线索。