Epigenetic pathology and therapy in Huntington's disease

亨廷顿氏病的简单遗传原因与大量的致病途径形成鲜明对比 受到突变的影响。其中一些途径水平的变化可能会持续下去，即使突变的等位基因 致病基因(HTT)可通过基因治疗或相关方法纠正。在第一次授予期间 在此期间，我们对HD模型的分析确定了几个潜在的治疗方向，包括密切相关的方向 到表观遗传学(转录调控因子NeUROD1、WNT和ELK-1)，以及与之相互作用的途径 表观基因组学变化(能量代谢和脂质生物化学)。其中一些影响仅限于 大脑中特定的细胞类型。我们还发现了突变HTT(MHTT)表达导致 神经发育障碍，改变大脑中细胞类型的分布。我们和其他人也 在人类群体中发现了大量得到重大支持的遗传变异 该变异对HD发病年龄(AOO)的影响。 在目前的提案中，我们基于这些发现检查干预措施的治疗潜力。我们会 以小鼠为靶点，测量干预如何改变转录、表观基因组、信号和 代谢组学。一项关键的创新是我们使用单细胞和空间分辨的方法来研究 不同类型的细胞对mHTT和治疗药物的反应不同。同样重要的是，我们将区分 体外诱导多能干细胞(IPSC)的特定细胞类型以检测细胞类型特异性在 人类细胞。使用基于系统生物学的方法，我们将寻找受影响的共同路径 通过遗传AOO修饰符，来自我们先前资助期的候选人和来自文献的领先。我们的 方法是高度创新的，因为它使用了具有单细胞和空间分辨率的尖端实验方法 以揭示在匀浆中检测不到的HD的某些方面。我们还计算积分多组分 来自单个细胞和大脑区域的数据(基因组学、表观基因组学、转录本、蛋白质和代谢物) 来发现治疗途径。这项研究具有重要意义，因为它试图指导治疗发现。 一种致命的神经退行性疾病。我们预计，我们工作的影响将延伸到高清以外， 通过提供如何测量和模拟细胞类型的特定神经退行性变的模型来识别治疗 接近了。

The simple genetic cause of Huntington’s disease contrasts starkly with the vast number of pathways that are affected by the mutation. Some of these pathway-level changes may persist even if the mutated allele of the disease-causing gene (HTT) can be corrected through gene therapy or related methods. During the first granting period, our analysis of HD models identified several potential therapeutic directions, including ones closely tied to epigenetics (the transcriptional regulators NEUROD1, WNTand ELK-1), as well as pathways that interact with epigenomic changes (energy metabolism and lipid biochemistry). Some of these effects were restricted to particular cell types in the brain. We also found evidence that mutant HTT (mHTT) expression causes neurodevelopmental impairments, changing the distribution of cell types in the brain. We and others have also identified a significant number of genetic variants in the human population for which there is significant support for an impact of that variant on HD age of onset (AOO). In the current proposal, we examine the therapeutic potential of interventions based on these findings. We will target these pathways in mice, measuring how interventions alter transcription, the epigenome, signaling and metabolomics. A critical innovation is our use of single-cell and spatially resolved methods to examine how responses to mHTT and therapeutics vary among different types of cells. Equally important, we will differentiate specific cell types from induced-pluripotent stem cells (iPSC) in vitro to examine cell-type specific effects in human cells. Using an approach based in systems biology we will look for common pathways that are affected by the genetic AOO modifiers, the candidates from our prior grant period and leads from the literature. Our approach is highly innovative, as it uses cutting edge experimental methods with single-cell and spatial resolution to reveal aspects of HD that cannot be detected in homogenates. We also computationally integrate multi-omic data (genomics, epigenomics, transcripts, proteins and metabolites) from the individual cells and brain regions to uncover therapeutic pathways. The research is highly significant, as it seeks to guide therapeutic discovery for an invariably fatal neurodegenerative disease. We expect that the impact of our work will extend beyond HD, by providing a model for how to measure and model cell-type specific neurodegeneration to identify therapeutic approaches.