Role of chromatin remodeling in Huntington's disease

描述（由申请人提供）：亨廷顿氏病（HD）是影响数百万美国人的几种神经退行性疾病之一。这些疾病中的许多与转录失调有关。在亨廷顿病的情况下，这种失调与病理学的相关性已经在HD的果蝇和小鼠模型中得到证实。HD是由亨廷顿蛋白中扩增的聚谷氨酰胺序列引起的，几项研究表明HD中的近端事件是扩增的polyQ蛋白破坏染色质重塑活性。用组蛋白去乙酰化酶（HDAC）抑制剂进行染色质治疗是目前正在开发的用于治疗亨廷顿病（HD）的最有前途的策略之一。这些和其他研究表明，一个更全面的方法，染色质治疗为基础的策略可能会被证明是更有益的。在这个建议中，我们将进行一个全面的分析，在HD设置的各种染色质重塑活动的治疗潜力。这些研究将有助于阐明突变型亨廷顿影响细胞转录的机制，以及治疗干预是恢复性的还是补偿性的。. 公共卫生相关性：许多神经退行性疾病的特征是基因表达中断。染色质是指控制基因产生的DNA和蛋白质的复合物，并且该复合物的结构在亨廷顿病和其他神经退行性疾病中被破坏。该项目的目标是开发新的治疗方法，以恢复染色质破坏到疾病前的状态，用于治疗亨廷顿病。

DESCRIPTION (provided by applicant): Huntington's Disease (HD) is one of several neurodegenerative diseases that affect millions of Americans. Many of these diseases are associated with transcriptional dysregulation. In the case of Huntington's disease, the relevance of this dysregulation to pathology has been demonstrated in Drosophila and mouse models of HD. HD is caused by an expanded poly- glutamine sequence in the huntingtin protein and several studies suggest that a proximal event in HD is the disruption of chromatin remodeling activities by the expanded polyQ protein. Chromatin therapy with Histone DeACetylase (HDAC) inhibitors is currently one of the most promising strategies being developed for the treatment of Huntington's disease (HD). These and other studies suggest that a more comprehensive approach to chromatin therapy based strategies may prove to be more beneficial. In this proposal, we will conduct a comprehensive analysis of the therapeutic potential of various chromatin-remodeling activities in an HD setting. These studies will help elucidate the mechanisms by which mutant Huntington affects cellular transcription and whether the therapeutic interventions are restorative or compensatory. . PUBLIC HEALTH RELEVANCE: Many neurodegenerative diseases are characterized by disruptions in gene expression. Chromatin refers to the complex of DNA and proteins that control gene production, and the structure of this complex is disrupted in Huntington's Disease and other neurodegenerative diseases. The goal of this project is to develop new therapies to restore chromatin disruptions to their pre-disease state for the treatment of Huntington's Disease.