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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：
10223442
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/10223442
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致病途径形成鲜明对比