Epigenetic pathology and therapy in Huntington's disease

亨廷顿病的表观遗传学病理学和治疗

• 批准号: 9121773
• 负责人: Ernest Fraenkel
• 金额: $ 5万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121773
• 关键词: Affinity Chromatography; Animals; Autopsy; Basal Ganglia; Binding; Brain; Brain Diseases; Cell Culture Techniques; Cells; Cessation of life; Chromatin; Chromatin Structure; DNA Methylation; Development; Disease; Disease model; Enzymes; Epigenetic Process; Evaluation; Functional disorder; Gene Expression; Genes; Genetic Transcription; Health; Histones; Human; Huntington Disease; Individual; Informatics; Intervention; Lead; Length; Ligand Binding; Link; Methodology; Methods; Modeling; Modification; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurons; Organism; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Positron-Emission Tomography; Preclinical Testing; Process; Ribosomes; Role; Route; Site; Stimulus; System; Systems Biology; Testing; Therapeutic; Therapeutic Intervention; Translating; Whole Organism; base; brain cell; brain tissue; cell type; chromatin modification; chromatin remodeling; genome-wide; human Huntingtin protein; induced pluripotent stem cell; insight; methylation pattern; mouse model; mutant; programs; promoter; response; transcriptome sequencing

 DESCRIPTION (provided by applicant): Transcriptional dysregulation is a pathognomonic feature of Huntington's disease (HD). Analysis of human brain at autopsy, PET ligand binding in pre-manifest HD patient brain and gene expression studies in numerous cell and animal HD models as well as human HD brain tissue all support the view that transcriptional dysregulation is an important feature of this disease. Several key questions arise in assessing the role of transcriptional dysregulation in HD. One important question is the mechanistic basis by which the presence of pathological Huntingtin (HTT) protein in HD brain leads to transcriptional dysfunction. An equally important question is the extent to which reversal or blockage of the transcriptional dysregulation program in HD can lead to a therapeutic benefit in this disease. While there have been many significant contributions towards understanding these questions, this proposal is focused on an extension of recent studies that we have carried out which implicate the epigenetic machinery of the cells of the basal ganglia and the cortex in the mechanistic basis of transcriptional dysregulation. Our recent observations on the specific patterns of histone marks and DNA methylation patterns altered at or near the promoters of downregulated genes provide very strong new support for a key role for epigenetic modulation in HD transcriptional dysregulation and pathology. Our findings provide further support for the concept that therapeutic intervention directed towards modulating the epigenetic machinery of the cell can be beneficial in impeding the pathology in HD. We propose here to extend these studies in depth to gain a deeper and more complete understanding of the programmatic and potentially causative changes caused by the expression of the pathological form of HTT. We will expand our analysis to examine additional models of HD and to examine individual cell types. We will also explore the role of mutant huntingtin in establishing the epigenetic patterns. Finally we will test methods for modifying the epigenetic patterns using cell based and whole organism studies, and we will determine the impact of these changes on HD transcriptional dysregulation and pathology. Our specific aims are therefore to: Aim 1: Establish baseline genome wide analyses of chromatin structure marks and transcription and Aim 2: Evaluate targets for potential therapeutic intervention through modulation of the pathological epigenetic program in HD. The development of a comprehensive and detailed analysis of chromatin modification in HD will provide a unique framework for understanding the role of epigenetic modification in nervous system function. The evaluation of potential efficacy of therapeutic interventions which operate through modulating chromatin modification pathways has the potential to have a decisive impact on the development of effective HD therapeutics by identifying the best potential targets for intervention and the extent to which HD pathology can be limited or perhaps reversed.

 描述（由适用提供）：转录失调是亨廷顿氏病（HD）的病理特征。在尸检时对人脑的分析，在尸检前HD患者脑中的PET配体结合以及许多细胞和动物HD模型中的基因表达研究以及人类高清脑组织都支持转录失调是该疾病的重要特征的观点。评估转录失调在HD中的作用时出现了几个关键问题。一个重要的问题是HD脑中病理亨廷汀（HTT）蛋白的存在导致转录功能障碍的机械基础。一个同样重要的问题是，高清转录失调程序的逆转或阻塞在多大程度上会导致这种疾病的治疗益处。尽管在理解这些问题方面有许多重要的贡献，但该提案集中在我们进行的最新研究的扩展上，这暗示了基本神经节细胞的表观遗传机制和在转录失调的机械基础上的皮质。我们最近对在下调基因的启动子或附近发生变化的组蛋白标记和DNA甲基化模式的特定模式的观察为表观遗传调节在HD转录失调和病理学中的关键作用提供了非常有力的新支持。我们的发现为概念提供了进一步的支持：针对调节细胞的表观遗传机制的治疗干预措施可能会受益于HD中的病理。我们将扩展分析以检查其他高清模型并检查单个细胞类型。我们还将探讨突变亨廷汀在建立表观遗传模式中的作用。最后，我们将测试使用基于细胞和整个生物体研究来修改表观遗传模式的方法，并确定这些变化对HD转录失调和病理学的影响。因此，我们的具体目的是：目标1：建立对染色质结构标记和转录的基线基因组广泛的分析和AIM 2：通过调节HD中染色质修饰的全面和详细分析的开发来评估潜在治疗干预的目标，将为理解表观遗传修饰在神经系统功能中的作用提供独特的框架。通过调节染色质修饰途径运行的治疗干预措施的潜在有效性的评估有可能对有效HD治疗的发展产生决定性的影响，这是通过确定干预的最佳潜在靶标，以及可以限制或可能反转HD病理的程度。