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: 8670779
• 负责人: J LAWRENCE MARSH
• 金额: $ 32.47万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670779
• 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; 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. .

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。在亨廷顿氏病的情况下，果蝇和HD小鼠模型已经证明了这种失调与病理学的相关性。 HD是由Huntingtin蛋白中的聚谷氨酰胺序列扩展引起的，几项研究表明，HD近端事件是膨胀的PolyQ蛋白会破坏染色质重塑活性。用组蛋白脱乙酰基酶（HDAC）抑制剂染色质治疗目前是为治疗亨廷顿氏病（HD）开发的最有希望的策略之一。这些研究和其他研究表明，基于染色质治疗的策略的一种更全面的方法可能被证明更有益。在此提案中，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亨廷顿突变体影响细胞转录以及治疗性干预措施的机制。 。

项目成果

A novel target for Huntington's disease: ERK at the crossroads of signaling. The ERK signaling pathway is implicated in Huntington's disease and its upregulation ameliorates pathology.

• DOI: 10.1002/bies.201100116
• 发表时间: 2012-02
• 期刊: BIOESSAYS
• 影响因子: 4
• 作者: Bodai, Laszlo;Marsh, J. Lawrence
• 通讯作者: Marsh, J. Lawrence

Morphometric analysis of Huntington's disease neurodegeneration in Drosophila.

• DOI: 10.1007/978-1-62703-438-8_3
• 发表时间: 2013-09
• 期刊: Methods in molecular biology
• 作者: Wan-Geun Song;MarianneR. Smith;A. Syed;T. Lukácsovich;BrettA. Barbaro;Judith M. Purcell;Doug J. Bornemann;J. Burke;J. L. Marsh