Role of chromatin remodeling in Huntington's disease

染色质重塑在亨廷顿病中的作用

• 批准号: 8272672
• 负责人: J LAWRENCE MARSH
• 金额: $ 41.33万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272672
• 关键词: Acetylation; Address; Affect; American; Behavior; Behavior assessment; Bilateral; Cell physiology; Chromatin; Chromosome Arm; Chromosomes; Complex; Corpus striatum structure; DNA; Disease; Disease model; Drosophila genus; Enzymes; Epigenetic Process; Equilibrium; Event; Exhibits; Female; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Histone Deacetylase Inhibitor; Histones; Huntington Disease; Individual; Injection of therapeutic agent; Lead; Link; Lysine; Methylation; MicroRNAs; Modeling; Mus; Nature; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathology; Patients; Pattern; Phosphorylation; Post-Translational Protein Processing; Production; Protein-Arginine N-Methyltransferase; Proteins; Recruitment Activity; Role; Specificity; Structure; Suggestion; Testing; Therapeutic; Therapeutic Intervention; Transferase; Treatment Efficacy; Treatment Protocols; Ubiquitin; Validation; Viral; arginyllysine; base; chromatin modification; chromatin remodeling; human Huntingtin protein; knock-down; mouse model; mutant; neuropathology; polyglutamine; protein complex; public health relevance; response; restoration; small hairpin RNA; uH2A

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.

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。许多这些疾病都与转录失调有关。在亨廷顿舞蹈病的情况下，这种失调与病理的相关性已经在果蝇和亨廷顿舞蹈病的小鼠模型中得到证实。亨廷顿舞蹈症是由亨廷顿蛋白中聚谷氨酰胺序列的扩展引起的，一些研究表明亨廷顿舞蹈症的近端事件是扩展的聚q蛋白破坏染色质重塑活动。用组蛋白去乙酰化酶（HDAC）抑制剂进行染色质治疗是目前治疗亨廷顿舞蹈病（HD）最有前途的策略之一。这些和其他研究表明，更全面的基于染色质治疗策略的方法可能更有益。在本提案中，我们将对HD环境中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。