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（由申请人提供）：转录失调是亨廷顿病 (HD) 的一个病理特征，对尸检中的人脑进行分析，在 HD 患者大脑中进行 PET 配体结合，以及在许多细胞和动物 HD 模型中进行基因表达研究。由于人类 HD 脑组织都支持这样的观点，即转录失调是这种疾病的一个重要特征，因此在评估转录失调在 HD 中的作用时出现了几个关键问题，其中一个重要问题是其机制基础。 HD 大脑中病理性亨廷顿蛋白 (HTT) 的存在会导致转录功能障碍，但同样重要的问题是逆转或阻断 HD 转录失调程序可以在多大程度上对该疾病产生治疗益处。对于理解这些问题做出了许多重大贡献，该提案的重点是我们最近进行的研究的延伸，这些研究暗示了基底神经节和皮质细胞的表观遗传机制在转录失调的机制基础中。关于下调基因启动子处或附近改变的组蛋白标记和 DNA 甲基化模式的特定模式，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，我们的研究结果为治疗干预的概念提供了进一步的支持。旨在调节细胞的表观遗传机制可能有利于阻止 HD 的病理学，我们在此建议深入扩展这些研究，以更深入、更全面地了解由病理表达引起的程序性和潜在致病性变化。形式我们将扩展我们的分析以检查其他 HD 模型并检查个体细胞类型，我们还将探索突变亨廷顿蛋白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的和修改表观遗传模式的方法。整个有机体研究，我们将确定这些变化对 HD 转录失调和病理学的影响，因此我们的具体目标是：目标 1：建立染色质结构标记和转录的基线全基因组分析，目标 2：评估潜在治疗的靶点。干涉通过对 HD 中的病理性表观遗传程序进行调节，对 HD 中的染色质修饰进行全面而详细的分析将为了解表观遗传修饰在神经系统功能中的作用评估所起作用的治疗干预措施提供一个独特的框架。通过调节染色质修饰途径，通过确定干预的最佳潜在目标以及限制或逆转亨廷顿病病理的程度，有可能对有效亨廷顿病疗法的开发产生决定性影响。