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)的一个病因学特征。对人脑的尸检分析、先期HD患者脑中的PET配体结合以及在大量细胞和动物HD模型以及人脑组织中的基因表达研究都支持转录失调是该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HD脑中病理性Huntingtin(HTT)蛋白的存在导致转录功能障碍的机制。一个同样重要的问题是，逆转或阻断HD的转录失调程序在多大程度上可以导致对这种疾病的治疗益处。虽然在理解这些问题方面已经有了许多重要的贡献，但这一建议侧重于我们最近进行的研究的扩展，这些研究涉及转录失调的机制基础中的基底节和皮质细胞的表观遗传机制。我们最近对组蛋白标记和DNA甲基化模式在下调基因启动子或附近改变的特定模式的观察，为表观遗传调控在HD转录调控和病理中的关键作用提供了非常有力的新支持。我们的发现进一步支持了这样的概念，即针对调节细胞表观遗传机制的治疗干预可以有益于阻止HD的病理。我们建议深入开展这些研究，以更深入和更完整地了解HTT病理形式的表达所引起的程序性和潜在的致病变化。我们将扩大我们的分析范围，以检查其他HD模型和单个细胞类型。我们还将探索突变的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，我们的具体目标是：目标1：建立染色质结构标记和转录的全基因组基线分析；目标2：通过调节HD的病理表观遗传程序，评估潜在的治疗干预靶点。对HD染色质修饰的全面而详细的分析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对治疗干预的潜在疗效进行评估，通过确定最好的潜在干预靶点以及HD病理可以被限制或逆转的程度，有可能对有效HD治疗的发展产生决定性影响。

 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.