Role of chromatin remodeling in Huntington's disease

描述(申请人提供)：亨廷顿病(HD)是影响数百万美国人的几种神经退行性疾病之一。这些疾病中的许多都与转录失调有关。在亨廷顿病的案例中，这种失调与病理的相关性已经在果蝇和HD的小鼠模型中得到了证明。HD是由Huntingtin蛋白中扩展的多谷氨酰胺序列引起的，一些研究表明HD的一个近端事件是扩展的PolyQ蛋白破坏染色质重塑活动。用组蛋白脱乙酰酶(HDAC)抑制剂进行染色质治疗是目前正在开发的治疗亨廷顿病(HD)的最有前途的策略之一。这些和其他研究表明，基于染色质治疗策略的更全面的方法可能被证明是更有益的。在这项提案中，我们将对HD环境下各种染色质重塑活动的治疗潜力进行全面分析。这些研究将有助于阐明突变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代偿性的。。 公共卫生相关性：许多神经退行性疾病的特点是基因表达中断。染色质是指DNA和控制基因产生的蛋白质的复合体，在亨廷顿病和其他神经退行性疾病中，这种复合体的结构被破坏。该项目的目标是开发新的治疗方法，将染色质的破坏恢复到疾病前的状态，用于亨廷顿病的治疗。

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.