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Epigenetic Regulation of Neuronal Cell Death

神经细胞死亡的表观遗传调控

基本信息

批准号：
8577189
负责人：
LEE J MARTIN
金额：
$ 35.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8577189
关键词：
Aberrant DNA Methylation Adult Age Amyotrophic Lateral Sclerosis Apoptosis Area Astrocytes Birds Brain Carbon Catalytic Domain Cell Culture Techniques Cell Line Cell Nucleus Cell Survival Cell model Cells Cytosine DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA Sequence DNA methyltransferase inhibition Data Dinucleoside Phosphates Discrimination Disease Down-Regulation Environmental Risk Factor Enzymes Epidemiologic Studies Epigenetic Process Fingerprint Gene Silencing Genes Genetic Genome Genomics Guanine Human Hypermethylation Incidence Individual Inherited Island Lead Maintenance Measures Mediating Methionine Methods Methylation Molecular Molecular Target Motor Cortex Motor Neurons Mus Mutation Nerve Degeneration Nerve Tissue Neurodegenerative Disorders Neuromuscular Diseases Neurons Nuclear Nucleic Acid Regulatory Sequences Pathogenesis Patients Pattern Physiology Positioning Attribute Procainamide Protein Isoforms Proteins RNA Interference Regulation Skeletal Muscle Specificity Spinal Cord Synapses Testing Transgenic Mice Up-Regulation Western Blotting Work acquired factor age related base case control cell type drug discovery effective therapy enzyme activity epigenome genome-wide immunoreactivity inorganic phosphate laser capture microdissection methyl group motor neuron degeneration mouse model nervous system disorder neuroligin 1 neuron loss novel novel strategies promoter racial and ethnic research study sciatic nerve skeletal socioeconomics

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with worldwide incidence and no racial, ethnic, or socioeconomic boundaries. Most ALS cases are sporadic with no known inherited component. Epidemiological studies implicate some environmental and acquired factors in its pathogenesis; however, previous genetic studies have been unable to uncover the genes involved in elucidating the molecular mechanisms of sporadic ALS. We hypothesize the aberrant epigenetic regulation of DNA contributes to the neurodegeneration in ALS. Specifically, we propose that aberrant silencing of neuronal or skeletal muscle synapse maintenance genes or cell survival genes by DNA methylation could be a critical factor in the cause of neurodegeneration in ALS. Our preliminary studies of human genomic DNA obtained from ALS patients and age-matched controls reveal differential patterns of hyper- and hypomethylation. CpG island microarrays have identified the neuroligin-1 gene promoter as being hypermethylated in human ALS nervous tissue. We also find increased levels of DNA methyltransferase isoforms (Dnmt1 and 3A) and 5- methylcytosine in human ALS nervous tissue. In cell culture and mouse models, we find that enforced expression and activity of Dnmts induce neuronal degeneration. We propose to conduct the following studies. In Specific Aim 1 we will perform additional CpG microarray analyses of human ALS and age-matched control nervous tissue and skeletal muscle to determine the specific genes that are hypermethylated or hypomethylated and to validate the patterns of gene methylation using alternative methods such as methylation- sensitive-restriction-fingerprinting and also demonstrate cell-type specificities in aberrant Dnmt expression and DNA methylation. In Specific Aim 2 we will test the hypothesis that neuroligin 1 silencing participates in the mechanisms of ALS through interneuronopathy and failure of synaptic inhibition. By studying the DNA methylation and gene silencing in ALS, we could identify novel cell-based, genome-based, and physiology-based mechanisms of ALS pathogenesis that could lead to novel strategies for treating ALS.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种致死性神经退行性疾病，在全球范围内发病，没有种族、民族或社会经济界限。大多数ALS病例是散发性的，没有已知的遗传成分。流行病学研究暗示了其发病机制中的一些环境和获得性因素;然而，先前的遗传学研究未能揭示参与阐明散发性ALS分子机制的基因。我们推测DNA的表观遗传调控异常有助于ALS的神经退行性变。具体来说，我们提出，异常沉默的神经元或骨骼肌突触维持基因或细胞存活基因的DNA甲基化可能是一个关键因素，在ALS的神经变性的原因。我们对ALS患者和年龄匹配的对照组的人类基因组DNA的初步研究揭示了高甲基化和低甲基化的差异模式。CpG岛微阵列已经确定了在人类ALS神经组织中，神经连接素-1基因启动子被高甲基化。我们还发现在人类ALS神经组织中DNA甲基转移酶亚型（Dnmt 1和3A）和5-甲基胞嘧啶的水平增加。在细胞培养和小鼠模型中，我们发现Dnmts的增强表达和活性诱导神经元变性。我们建议进行以下研究。在特定目标1中，我们将对人类ALS和年龄匹配的对照神经组织和骨骼肌进行额外的CpG微阵列分析，以确定高甲基化或低甲基化的特定基因，并使用替代方法（如甲基化敏感限制性指纹图谱）验证基因甲基化模式，并证明异常Dnmt表达和DNA甲基化的细胞类型特异性。在具体目标2中，我们将测试神经连接素1沉默通过神经元间病变和突触抑制失败参与ALS机制的假设。通过研究ALS中的DNA甲基化和基因沉默，我们可以确定ALS发病机制的新的基于细胞、基于基因组和基于生理学的机制，这可能导致治疗ALS的新策略。