Epigenetic pathology and therapy in Huntington's disease

亨廷顿氏病的简单遗传原因与亨廷顿氏病的大量遗传途径形成鲜明对比。 受到突变的影响。这些途径水平的变化中的一些可能持续存在，即使突变的等位基因的突变， 致病基因（HTT）可以通过基因治疗或相关方法来纠正。在第一次授予 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， 表观遗传学（转录调节因子NEUROD 1，WNT和ELK-1），以及与 表观基因组变化（能量代谢和脂质生物化学）。其中一些影响仅限于 大脑中的特定细胞类型。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 在人群中发现了大量的遗传变异， 该变异对HD发病年龄（AOO）的影响。 在目前的建议中，我们研究了基于这些发现的干预措施的治疗潜力。我们将 在小鼠中靶向这些途径，测量干预如何改变转录，表观基因组，信号传导和 代谢组学一个关键的创新是我们使用单细胞和空间分辨的方法来研究如何 对mHTT和治疗剂的反应在不同类型的细胞中不同。同样重要的是， 体外诱导多能干细胞（iPSC）的特定细胞类型，以检查细胞类型特异性作用， 人体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途径 通过遗传AOO修饰剂，从我们以前的资助期和领导的文献候选人。我们 这种方法是高度创新的，因为它使用了具有单细胞和空间分辨率的尖端实验方法 以揭示不能在匀浆中检测到的HD方面。我们还计算整合多组学 来自单个细胞和大脑区域的数据（基因组学、表观基因组学、转录物、蛋白质和代谢物） 来揭示治疗途径这项研究非常重要，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希望我们的工作的影响将超越HD， 通过提供如何测量和模拟细胞类型特异性神经变性的模型， 接近。

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.