对纹状体疾病的机制解释-猫眼课题宝

对纹状体疾病的机制解释

批准号：

7900465

负责人：

ELIZABETH A THOMAS

金额：

$42.73万

依托单位：

SCRIPPS RESEARCH INSTITUTE, THE

依托单位国家：

美国

项目类别：

财政年份：

2002

资助国家：

美国

项目状态：

已结题

起止时间：

2002-06-01 至 2012-07-31

来源：

https://reporter.nih.gov/project-details/7900465

关键词：

Adult Base Sequence Behavioral Assay Bilateral Binding Biological Assay Biological Models CAG repeat Candidate Disease Gene Cell Survival Cells Central Nervous System Diseases Code Corpus striatum structure DNA Microarray Chip Detection Disease Disease model Equipment and supply inventories Exhibits Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Goals Huntington Disease Immediate-Early Genes In Vitro Injection of therapeutic agent Knock-in Mouse Knowledge Length Measures Mediator of activation protein Metabolic Microarray Analysis Molecular Molecular Profiling Motor Mus Neurons Nuclear Pathology Phenotype Physiological Play Promoter Regions Proteins RNA Interference Role Specificity Testing Therapeutic Tissues Transcriptional Regulation Transgenic Mice Validation base chromatin immunoprecipitation design disease phenotype efficacy testing genome wide association study genome-wide glycosylation human Huntingtin protein human subject in vivo knock-down loss of function mRNA Expression molecular phenotype mouse model mutant novel overexpression polyglutamine small hairpin RNA transcription factor vector

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Alterations in gene expression are apparent in most CNS disorders, ranging from dysregulated expression of disease genes themselves to pathology-induced activation of immediate early genes and delayed secondary effects on transcription. In particular, transcriptional dysregulation has emerged as a central pathogenic mechanism in Huntington's disease (HD), which is associated with neuropathological changes predominantly in the striatum. Accordingly, mRNAs of genes showing enriched expression in the striatum are markedly reduced in HD mouse models and human subjects. The mechanisms for this dysregulation and for striatal-specificity of neuronal pathology remain unknown. We have previously found that seven transcription factors (TFs) exhibiting striatal-enriched expression are present in adult CNS and are downregulated in HD. We have evidence that at least two such factors, Bcl11b and Foxp1, act to regulate gene expression in the striatum and interact with the huntingtin (Htt) protein. Hence, our hypothesis is that decreased function of these striatal TFs due to the presence of mutant Htt is integrally associated with cell- autonomous transcriptional deficits in HD. This proposal is aimed at testing the roles of striatal TFs in controlling gene expression under normal and disease states. Such knowledge will have paramount relevance to HD and other striatal disorders. Studies in Aim 1 will test physiological roles of striatal transcription factors in HD model systems. This will be accomplished by manipulating transcription factor levels through overexpression and RNA interference in striatal cells and in R6/2 transgenic mice. Studies in Aim 2 will identify gene targets specifically for Bcl11b and Foxp1 by performing microarray analysis on the HD striatal cells and R6/2 mice from Aim 1. In addition, we will identify interactions of Bcl11b and Foxp1 with target genes and genome-wide promoter regions using chromatin-immunoprecipitation in combination with DNA microarray analysis. The results of these studies should have high therapeutic relevance, such that novel compounds designed to target striatal transcription factors would reverse striatal deficits without exhibiting widespread effects in the CNS. ARRA Request: 2 R01 NS044169-06A2 Thomas, Elizabeth A.

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