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Towards Mechanistic Explanations of Striatal Disorders

对纹状体疾病的机制解释

基本信息

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
起止时间：
2002-06-01 至 2012-07-31
项目状态：
已结题

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

项目摘要

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.

基因表达的改变在大多数中枢神经系统疾病中是明显的，范围从失调疾病基因本身的表达与病理诱导的立即早期基因的激活有关，对转录的延迟次级效应。特别是，转录失调已经成为一种亨廷顿舞蹈病（HD）的中枢致病机制，与神经病理学相关，变化主要发生在纹状体。因此，在大肠杆菌中显示富集表达的基因的mRNA，在HD小鼠模型和人类受试者中纹状体的显著减少。这种机制调节异常和神经元病理学的纹状体特异性仍然未知。我们之前发现显示纹状体富集表达的七种转录因子（TF）存在于成人CNS中，在HD中下调。我们有证据表明，至少有两个这样的因素，Bcl 11b和Foxp 1，基因在纹状体的表达，并与亨廷顿蛋白（Htt）的蛋白质相互作用。因此，我们假设，由于突变型Htt的存在，这些纹状体TF的功能降低与细胞凋亡密切相关。 HD中的自主转录缺陷。这项提议旨在测试纹状体TF在以下方面的作用：控制正常和疾病状态下的基因表达。这些知识将具有至关重要的意义 HD和其他纹状体疾病。目标1的研究将测试纹状体转录因子的生理作用在HD模型系统中。这将通过操纵转录因子水平来实现，在纹状体细胞和R6/2转基因小鼠中的过表达和RNA干扰。目标2中的研究将通过对HD纹状体进行微阵列分析，细胞和来自Aim 1的R6/2小鼠。此外，我们还将鉴定Bcl 11b和Foxp 1与靶基因的相互作用和全基因组启动子区的研究分析.这些研究的结果应该具有高度的治疗相关性，使得新的化合物可以用于治疗。旨在靶向纹状体转录因子的药物将逆转纹状体缺陷，对CNS的影响。 ARRA请求：2 R 01 NS 044169 - 06 A2托马斯，伊丽莎白A.

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular profiles of schizophrenia in the CNS at different stages of illness.

DOI：
10.1016/j.brainres.2008.08.023
发表时间：
2008-11-06
期刊：
Brain research
影响因子：
2.9
作者：
Narayan S;Tang B;Head SR;Gilmartin TJ;Sutcliffe JG;Dean B;Thomas EA
通讯作者：
Thomas EA

Genome-wide identification of Bcl11b gene targets reveals role in brain-derived neurotrophic factor signaling.

Bcl11b基因靶标的全基因组鉴定揭示了在脑衍生的神经营养因子信号中的作用。

DOI：
10.1371/journal.pone.0023691
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Tang B;Di Lena P;Schaffer L;Head SR;Baldi P;Thomas EA
通讯作者：
Thomas EA

From pharmacotherapy to pathophysiology: emerging mechanisms of apolipoprotein D in psychiatric disorders.

从药物治疗到病理生理学：载脂蛋白 D 在精神疾病中的新兴机制。

DOI：
10.2174/1566524033479681
发表时间：
2003
期刊：
Current molecular medicine
影响因子：
2.5
作者：
Thomas,EA;Copolov,DL;Sutcliffe,JG
通讯作者：
Sutcliffe,JG

Differential age- and disease-related effects on the expression of genes related to the arachidonic acid signaling pathway in schizophrenia.

DOI：
10.1016/j.psychres.2011.09.026
发表时间：
2012-04-30
期刊：
PSYCHIATRY RESEARCH
影响因子：
11.3
作者：
Tang, Bin;Capitao, Cristina;Dean, Brian;Thomas, Elizabeth A.
通讯作者：
Thomas, Elizabeth A.

In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons.

在纹状体而非皮层神经元中表达突变亨廷顿蛋白的小鼠中，揭示了体内细胞自主转录异常。

DOI：
10.1093/hmg/ddq548
发表时间：
2011
期刊：
Human molecular genetics
影响因子：
3.5
作者：
Thomas,ElizabethA;Coppola,Giovanni;Tang,Bin;Kuhn,Alexandre;Kim,SoongHo;Geschwind,DanielH;Brown,TimothyB;Luthi-Carter,Ruth;Ehrlich,MichelleE
通讯作者：
Ehrlich,MichelleE