Epigenetic pathology and therapy in Huntington's disease

亨廷顿病的表观遗传学病理学和治疗

基本信息

批准号：
10411989
负责人：
Ernest Fraenkel
金额：
$ 40.85万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10411989
关键词：
ATAC-seq Affect Age Age of Onset Alleles Animal Model BETA2 protein Biological Assay Biological Models Brain Brain region Cell Culture Techniques Cell Differentiation process Cell Nucleus Cell model Cells Corpus striatum structure Data Disease Disease model ELK1 gene Energy Metabolism Epigenetic Process Genes Genetic Genetic Transcription Genomics Goals Grant Human Huntington Disease Huntington protein In Vitro Individual Inherited Intervention Investigation Link Lipid Biochemistry Lipids Literature Measures Methods Modeling Molecular Multiomic Data Mus Mutate Mutation Nerve Degeneration Neurodegenerative Disorders Neurodevelopmental Impairment Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phosphotransferases Population Prostaglandin D2 Proteomics Research Resolution Signal Transduction Symptoms System Systems Biology Technology Testing Therapeutic Therapeutic Intervention Transcript Variant Work base cell type chromatin protein data integration disease-causing mutation effective therapy epigenome epigenomics gene therapy genetic variant group intervention improved in vivo induced pluripotent stem cell innovation insight metabolomics mutant nervous system disorder novel strategies novel therapeutic intervention programs protein metabolite response stem cell model therapeutically effective transcriptome sequencing

项目摘要

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.

亨廷顿氏病的简单遗传原因与大量的途径形成鲜明对比受突变的影响。这些途径级别的某些变化也可能会持续存在可以通过基因治疗或相关方法纠正引起疾病的基因（HTT）。在第一次授予期间时期，我们对HD模型的分析确定了几个潜在的治疗方向，包括紧密绑定的方向进行表观遗传学（转录调节剂NeuroD1，Wntand Elk-1），以及与之相互作用的途径表观基因组变化（能量代谢和脂质生物化学）。其中一些效果仅限于大脑中的特定细胞类型。我们还发现了突变htt（MHTT）表达引起的证据神经发育障碍，改变了大脑中细胞类型的分布。我们和其他人也有确定了人口中有大量支持的大量遗传变异为了对该变体的影响对发病的高清年龄（AOO）。在当前的建议中，我们根据这些发现检查了干预措施的治疗潜力。我们将靶向小鼠中的这些途径，测量干预措施如何改变转录，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解决方法来检查如何对MHTT和疗法的反应在不同类型的细胞之间有所不同。同样重要的是，我们将区分在体外诱导诱导的干细胞（IPSC）的特定细胞类型，以检查细胞类型的特异性效应人类细胞。使用基于系统生物学的方法，我们将寻找受影响的常见途径通过遗传AOO修饰符，我们以前的赠款时期的候选人并从文献中汲取了主导地位。我们的方法具有高度创新性，因为它使用具有单细胞和空间分辨率的尖端实验方法揭示在匀浆中无法检测到的高清方面。我们还计算整合多摩变来自单个细胞和大脑区域的数据（基因组学，表观基因组学，成绩单，蛋白质和代谢产物）发现治疗途径。该研究非常重要，因为它试图指导治疗发现对于不变的致命神经退行性疾病。我们预计我们的工作的影响将超出高清，通过提供如何测量和建模细胞类型的特定神经变性的模型以识别治疗方法。