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The role of capicua in spinocerebellar ataxia type 1

Capicua 在 1 型脊髓小脑共济失调中的作用

基本信息

批准号：
7243457
负责人：
John David Fryer
金额：
$ 4.88万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7243457
关键词：
Affect Age Ataxia Behavioral Binding Bioinformatics Biological Biological Assay Brain Stem Breeding Cerebellum Complex Coupled Data Data Set Development Disease Drosophila genus Electrophoretic Mobility Shift Assay Embryo Embryonic Development Fellowship Functional disorder Gene Expression Generations Genes Glutamine Goals Immunofluorescence Immunologic Immunohistochemistry Immunoprecipitation Individual Knock-in Mouse Knockout Mice Laboratories Lead Light Localized Mammals Memory Messenger RNA Microarray Analysis Modeling Molecular Molecular Sieve Chromatography Mus Mutant Strains Mice Names Nerve Degeneration Neurodegenerative Disorders Neurons Onset of illness Orthologous Gene Overlapping Genes Pathogenesis Pathway interactions Pattern Phenotype Physiologic pulse Protein Family Protein Overexpression Proteins Pulse taking Purkinje Cells Reverse Transcriptase Polymerase Chain Reaction Role Running Spinocerebellar Ataxias Testing Two-Hybrid System Techniques Type 1 Spinocerebellar Ataxia Western Blotting Yeasts ataxin-1 behavior measurement chromatin immunoprecipitation disease phenotype gain of function in vivo insight member motor learning mutant novel polyglutamine promoter research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to determine the role of capicua (Cic) in spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease caused by a polyglutamine expansion in Ataxin-1 (Atx-1). Cic is a transcriptional represser in Drosophila and preliminary results show that Cic interacts with Atx-1, co-localizes to Purkinje neurons that degenerate in SCA1, and its level is reduced in Atx-1-null mice. I will first analyze the expression of Cic during development in wild-type and Atx-1-null mice. I will generate and characterize Cic- null mice (Cic-/-) to determine the normal role of Cic in vivo and to determine its role in the normal function of Atx-1 (when crossed to Atx-1-null mice). Cic-null mice will be crossed to a knock-in model of SCA1 to determine whether and how Cic affects SCA1 pathogenesis. Given Cic's role as a transcriptional represser, I will investigate gene expression changes by microarray analysis in Cic and Cic-/- mice. Changes in Cic mutants will be compared to those of Atx-1-null and SCA1 knock-in mice (currently being performed by other laboratory members) to pinpoint those changes most relevant to SCA1 and Atx-1 function. This project will establish the role of Cic in mammals and in the normal function of Atx-1 and in SCA1 pathogenesis.

描述（由申请人提供）：本项目的目的是确定capicua（Cic）在脊髓小脑共济失调1型（SCA 1）中的作用，SCA 1是一种由Ataxin-1（Atx-1）中的多聚谷氨酰胺扩增引起的神经退行性疾病。Cic是果蝇中的转录抑制因子，初步结果表明，Cic与Atx-1相互作用，共定位于SCA 1中退化的浦肯野神经元，并且其水平在Atx-1缺失小鼠中降低。我将首先分析Cic在野生型和Atx-1缺失小鼠发育过程中的表达。本人将产生并表征Cic-敲除小鼠（Cic-/-）以确定Cic在体内的正常作用并确定其在Atx-1的正常功能中的作用（当与Atx-1敲除小鼠杂交时）.将Cic缺失小鼠与SCA 1的敲入模型杂交，以确定Cic是否以及如何影响SCA 1发病机制。鉴于Cic作为转录抑制因子的作用，我将通过Cic和Cic-/-小鼠的微阵列分析来研究基因表达的变化。将Cic突变体的变化与Atx-1-null和SCA 1敲入小鼠的变化进行比较（目前由其他实验室成员进行），以确定与SCA 1和Atx-1功能最相关的变化。该项目将确定Cic在哺乳动物中的作用，以及在Atx-1的正常功能和SCA 1发病机制中的作用。