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Role of DNA methyltransferases in Huntington's disease

DNA 甲基转移酶在亨廷顿病中的作用

基本信息

批准号：
9919649
负责人：
Hiroko Yano
金额：
$ 42.72万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919649
关键词：
Aberrant DNA Methylation Address Aging Animals Atrophic Attenuated Automobile Driving Behavior Biochemical Biological Brain Brain Diseases Cell Line Cells Cessation of life Chromatin Structure Cognition Cognition Disorders Cognitive Cognitive deficits Corpus striatum structure DNA DNA Methylation DNA Methylation Regulation DNA Methyltransferase Inhibitor DNA Modification Methylases DNA Sequence Alteration DNA methyltransferase inhibition Data Development Disease Disease Progression Disease model Enzymes Epigenetic Process Event Foundations Functional disorder Gene Expression Gene Expression Regulation Gene Silencing Gene Targeting Genes Genetic Genetic Transcription Genomics Goals Human Huntington Disease Huntington gene In Vitro Knockout Mice Learning Libraries Link Mediating Memory Mental Depression Mental disorders Modeling Modification Molecular Molecular Abnormality Movement Mus Mutation Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurologic Symptoms Neuronal Dysfunction Neurons Pathogenesis Pathway interactions Patients Pattern Pharmacology Physiological Play Proteins Publishing RNA Regulation Role Synaptic plasticity System Techniques Testing Therapeutic Toxic effect Transcription Alteration base behavioral phenotyping brain tissue cell type cytotoxicity epigenetic drug experimental study genome-wide genome-wide analysis histone modification in vivo in vivo Model innovation motor disorder mouse model mutant neuron loss neuropathology neuroprotection neurotoxicity new therapeutic target novel polyglutamine prevent promoter protein protein interaction therapeutic development therapeutic target

项目摘要

ABSTRACT Huntington’s disease (HD) is a devastating and invariably fatal neurodegenerative disease characterized by progressive atrophy and loss of specific neurons in the striatum and cortex, leading to motor, cognitive, and psychiatric disorders. The underlying disease mechanism remains poorly understood, and currently, no cure exists for this disease. There is an urgent need to understand the molecular mechanisms driving the death of HD neurons, so that these mechanisms can be harnessed to save these dying neurons. Transcriptional dysregulation is an early molecular abnormality in the course of HD and is thought to contribute to neurodegeneration and disease progression. Although emerging evidence indicates altered patterns of several different epigenetic modifications in HD, key epigenetic modifications that have a causal role in transcriptional changes and neurodegeneration remain largely unknown. DNA methylation, a major epigenetic modification, has recently been shown to be perturbed in mutant Htt-expressing cells and brains of HD patients. Importantly, our recent findings suggest that DNA methyltransferases (DNMTs), enzymes that catalyze DNA methylation, are of functional importance in mutant HD protein (huntingtin)-induced neurotoxicity. The fundamental objective of this proposal is to identify the molecular regulation and role of DNMTs in neuronal dysfunction and death, using mouse and human cultured neurons as well as mouse models of HD. Our hypothesis is that abnormal DNA methylation is a dominant epigenetic event in HD, which drives the dysregulation of genes important for neuronal function and survival, thereby contributing to neuronal dysfunction and death in HD. Targeting this epigenetic pathway may therefore prevent disease progression. To test this hypothesis, we will pursue the following specific aims: 1) Determine how mutant Htt induces aberrant DNA methylation with a focus on DNMT function; 2) Determine the role of DNMTs in HD pathogenesis in mice in vivo; and 3) Identify the mechanism of DNMT inhibition-mediated neuroprotection in mutant Htt-expressing neurons in vitro and in vivo. We will take innovative approaches to isolate cell-type specific RNA and DNA from mouse brain to determine HD-specific DNA methylation and transcription changes in disease-vulnerable neurons in vivo. Our contribution here is expected to establish the critical role of DNMTs in HD pathogenesis using a disease-relevant neuronal system and genetic mouse models in vivo, with the long-term goal of discovering potential therapeutic targets to prevent neurodegeneration in HD. Given the observation of altered transcription and DNA methylation in other neurodegenerative diseases, psychiatric disorders, aging, and learning and memory, the proposed studies have implications for a wide-range of human nervous system conditions as well as normal brain function. Together, our examination of a novel epigenetic mechanism underlying mutant Htt-induced transcriptional dysregulation and neurodegeneration will provide answers to fundamental questions in the field of neurodegenerative diseases.

抽象的亨廷顿舞蹈症 (HD) 是一种毁灭性且致命的神经退行性疾病，其特征是通过纹状体和皮质中特定神经元的进行性萎缩和丧失，导致运动、认知和功能障碍精神疾病。潜在的疾病机制仍知之甚少，目前尚无治愈方法针对这种疾病而存在。迫切需要了解驱动死亡的分子机制 HD 神经元，以便可以利用这些机制来拯救这些垂死的神经元。转录的失调是 HD 病程中的一种早期分子异常，被认为有助于神经退行性变和疾病进展。尽管新出现的证据表明一些模式发生了改变 HD 中不同的表观遗传修饰，在转录中具有因果作用的关键表观遗传修饰变化和神经退行性变仍然很大程度上未知。 DNA甲基化是一种主要的表观遗传修饰，最近被证明在 HD 患者的突变 Htt 表达细胞和大脑中受到干扰。重要的是，我们最近的研究结果表明，DNA 甲基转移酶 (DNMT) 是催化 DNA 甲基化的酶，在突变 HD 蛋白（亨廷顿蛋白）诱导的神经毒性中具有重要的功能。的根本目标该提案旨在确定 DNMT 在神经元功能障碍和死亡中的分子调节和作用，使用小鼠和人类培养的神经元以及 HD 小鼠模型。我们的假设是异常 DNA 甲基化是 HD 中的一个显性表观遗传事件，它会导致重要基因的失调。神经元功能和存活，从而导致 HD 中神经元功能障碍和死亡。以此为目标因此，表观遗传途径可能会阻止疾病进展。为了检验这个假设，我们将追求以下具体目标： 1) 确定突变体 Htt 如何诱导异常 DNA 甲基化，重点关注 DNMT 功能; 2）确定DNMTs在小鼠HD发病机制中的体内作用； 3）确定其机制 DNMT 抑制介导的突变 Htt 表达神经元的体外和体内神经保护。我们将采取从小鼠大脑中分离细胞类型特异性 RNA 和 DNA 以确定 HD 特异性的创新方法体内疾病易感神经元的 DNA 甲基化和转录变化。我们在这里的贡献是预计利用疾病相关神经系统确定 DNMT 在 HD 发病机制中的关键作用和体内遗传小鼠模型，长期目标是发现潜在的治疗靶点以预防 HD 中的神经变性。考虑到在其他细胞中观察到转录和 DNA 甲基化的改变神经退行性疾病、精神疾病、衰老以及学习和记忆，拟议的研究对多种人类神经系统状况以及正常大脑功能的影响。一起，我们对突变体 Htt 诱导的转录失调的新型表观遗传机制的研究神经退行性疾病将为神经退行性疾病领域的基本问题提供答案疾病。