Erforschung transkriptioneller Dysregulation bei Morbus Huntington: Durch Genom-weite Kartierung von Genen, deren Promotoren direkt vom Protein Huntingtin beeinflusst werden, sollen Erkenntnisse über den Umfang und die Mechanismen von Transkriptionsstörun

亨廷顿病转录失调的研究：通过对启动子直接受亨廷顿蛋白影响的基因进行全基因组图谱，可以深入了解转录失调的程度和机制

• 批准号: 23691316
• 负责人: Dr. Florian Then
• 金额: --
• 依托单位: McKinsey
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/23691316?language=en
• 关键词: Erforschung; transkriptioneller; Dysregulation; bei; Morbus

Huntington s disease (HD) is an inherited neurodegenerative disorder that causes cognitive decline and progressive motor impairment in affected individuals and eventually leads to death. HD is caused by an expansion of a GAG triplet repeat sequence in the gene IT 15, coding for a polyglutamine stretch in the protein huntingtin. The exact mechanism by which mutant huntingtin causes cellular dysfunction and cell death is unknown. Transcriptional deregulation has emerged as an important contributor to pathogenesis in HD. Huntingtin has been shown to interact with a number of transcription factors and analyses of gene expression patterns revealed alterations in messenger RNA levels of hundreds of genes in brain and peripheral tissues in HD. It is not known what proportion of the observed changes in messenger RNA levels results from direct effects of mutant huntingtin on gene promoters. In order to address this question, we will use recently developed ChlP-on-chip technology, combining chromatin immuno-precipitation (ChIP) and promoter microarray analysis. This approach allows for genome-wide in vivo mapping of gene promoters directly affected by huntingtin which in turn should help identify specific transcriptional pathways in vivo and provide new insights into the pathogenesis of HD. Moreover, comprehensive identification of gene targets of mutant huntingtin could greatly facilitate the search for biomarkers and specific therapies in HD.

亨廷顿病 (HD) 是一种遗传性神经退行性疾病，会导致受影响个体认知能力下降和进行性运动障碍，并最终导致死亡。 HD 是由基因 IT 15 中 GAG 三联体重复序列的扩展引起的，IT 15 编码亨廷顿蛋白中的多谷氨酰胺片段。突变型亨廷顿蛋白导致细胞功能障碍和细胞死亡的确切机制尚不清楚。转录失调已成为 HD 发病机制的一个重要因素。亨廷顿蛋白已被证明与许多转录因子相互作用，并且对基因表达模式的分析揭示了 HD 患者大脑和外周组织中数百个基因的信使 RNA 水平的变化。目前尚不清楚观察到的信使 RNA 水平变化中有多少比例是由突变亨廷顿蛋白对基因启动子的直接影响造成的。为了解决这个问题，我们将使用最近开发的 ChlP-on-chip 技术，结合染色质免疫沉淀 (ChIP) 和启动子微阵列分析。这种方法可以对受亨廷顿蛋白直接影响的基因启动子进行全基因组体内定位，这反过来又有助于识别体内特定的转录途径，并为 HD 的发病机制提供新的见解。此外，全面鉴定突变亨廷顿蛋白的基因靶点可以极大地促进HD生物标志物和特异性疗法的寻找。