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.
The goals of this application are to identify mechanisms of gene expression associated with the functions of the striatum under normal and pathological conditions. Transcriptional dysregulation has emerged as a central pathogenic mechanism in Huntington's disease (HD), which is associated with neuropathological changes predominantly in the striatum. We have found a decrease in the expression of several striatal transcription factors in HD and have shown that at least two of these are essential to HD pathology in model systems. We propose to further characterize mechanisms of gene expression control and identify target genes for these factors. These studies should have high therapeutic relevance, such that novel compounds designed to target striatal transcription factors would reverse striatal deficits without exhibiting pleiotropic effects in the CNS.
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