Epigenetic pathology and therapy in Huntington's disease

 描述（由申请人提供）：转录失调是亨廷顿病（HD）的一个特征。尸检时对人脑的分析、表现前HD患者脑中的PET配体结合以及许多细胞和动物HD模型以及人HD脑组织中的基因表达研究都支持转录失调是这种疾病的重要特征的观点。在评估转录失调在HD中的作用时出现了几个关键问题。一个重要的问题是机制的基础上，病理亨廷顿（HTT）蛋白的存在下，在HD脑导致转录功能障碍。一个同样重要的问题是逆转或阻断HD中的转录失调程序在多大程度上可以导致这种疾病的治疗益处。虽然有许多重大的贡献对理解这些问题，这个建议是集中在最近的研究，我们已经进行了牵连的表观遗传机制的基底神经节和皮质的转录失调的机制基础的延伸。我们最近的观察组蛋白标记的特定模式和DNA甲基化模式改变的启动子或附近的下调基因提供了非常强有力的新的支持，在HD转录失调和病理的表观遗传调节的关键作用。我们的研究结果提供了进一步的概念，即针对调节细胞的表观遗传机制的治疗干预可以有益于阻碍HD的病理。在这里，我们建议深入扩展这些研究，以获得更深入和更完整的了解HTT的病理形式的表达所引起的程序性和潜在的因果关系的变化。我们将扩大我们的分析，以检查HD的其他模型，并检查单个细胞类型。我们还将探讨突变亨廷顿蛋白在建立表观遗传模式中的作用。最后，我们将使用基于细胞和整个生物体的研究来测试用于修改表观遗传模式的方法，并且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：通过调节HD中的病理表观遗传程序来评估潜在治疗干预的靶点。对HD中染色质修饰的全面和详细分析的发展将为理解表观遗传修饰在神经系统功能中的作用提供一个独特的框架。通过调节染色质修饰途径发挥作用的治疗干预措施的潜在疗效评价，有可能通过确定最佳的潜在干预靶点以及HD病理学可以限制或逆转的程度，对有效HD治疗药物的开发产生决定性影响。

 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.