Epigenetic Markers in Huntington's disease Brain

亨廷顿病大脑中的表观遗传标记

基本信息

批准号：
8291969
负责人：
RICHARD H MYERS
金额：
$ 62.36万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8291969
关键词：
Address Age of Onset Appearance Biological Markers Blood Blood Cells Blood specimen Brain CAG repeat CD4 Positive T Lymphocytes Cell Nucleus Cerebral cortex Cerebrum Cessation of life ChIP-seq Chorea Clinical Trials Cognitive Complement Computing Methodologies Corpus striatum structure Data Diagnosis Diffuse Disease Disease Progression Drug Evaluation Epigenetic Process Exons Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genome Mappings Genomics Glutamates Goals Hereditary Disease Histone H3 Histones Human Huntington Disease Impaired cognition Investigation Lymphocyte Lysine Maps Measures Memory Loss Messenger RNA Methods Methylation Modeling Molecular Molecular Target Movement Mutation Neurodegenerative Disorders Neurons Nuclear Inclusion Outcome Study Pathogenesis Pathology Pathway interactions Patients Pattern Pharmaceutical Preparations Prefrontal Cortex Process Research Resources Role SNP genotyping Sampling Signal Transduction Site Sorting - Cell Movement Staging Synapses System Techniques Technology Tissues Transcription Initiation Site Trinucleotide Repeat Expansion Ubiquitin brain cell comparative density disorder control excitotoxicity gain of function genome wide association study genome-wide genome-wide analysis histone modification human Huntingtin protein insight mind control multicatalytic endopeptidase complex mutant neuron loss novel promoter skills transmission process

项目摘要

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a fatal, autosomal dominant neurodegenerative disorder caused by an expanded CAG tract in the HD gene that results in gradual loss of memory, cognitive skills and normal movements. Multiple lines of research point to dysregulated transcription as a prevailing feature of HD pathology and suggest that altered histone modification by the mutant protein (Htt) may contribute to this process. However, thus far there has been no genome-wide analysis of histone modifications in human HD brain. The studies proposed here apply novel genomic technology to the search for epigenetic signatures in HD brains with the goal of gaining insight into HD pathogenesis. Our proposal capitalizes on two unique resources: (1) a novel FACS-ChIP-seq method which we will apply to establish and compare the methylomes of neurons from HD and control brains; and (2) a unique sample of HD brains, including a set matched for CAG repeat expansion (range 42-44 repeats) but onset ages differing by 30 years or more. The brains have been extensively neuropathologically characterized for degree of both striatal and cortical involvement. Since we found that histone H3 methylation markings in HD brains overlap highly with the signal in CD4+ cells, we are also comparing the altered epigenetic signature seen in HD brain to that in blood samples at varying stages of disease (presymptomatic, early and advanced HD) as this may offer a novel epigenetic biomarker in HD blood. Such biomarkers are of translational significance for the evaluation of drug treatments to realign the disrupted gene expression. We have preliminary data using the FACS-ChIP-Seq method in six HD prefrontal cortex samples and eleven normal controls, which provides tantalizing evidence for the significance of the proposed studies and demonstrates our capabilities to apply the techniques and to meaningfully interpret the findings. Our approach represents the most comprehensive analysis to date addressing the role of histone methylation in HD pathogenesis. Regardless of outcome, these studies will provide critical new insights into the molecular pathways of HD pathogenesis and may also uncover novel molecular targets for HD treatment. The high translational impact of this proposal is increased by our proposal to identify and characterize a unique histone methylation biomarker in HD blood cells. If successful, identification of such a biomarker will greatly facilitate clinical trials for novel HD therapies and offers a novel method to evaluate whether new drug treatments rectify disrupted gene expression.

描述（由申请人提供）：亨廷顿病 (HD) 是一种致命的常染色体显性神经退行性疾病，由 HD 基因中的 CAG 束扩张引起，导致记忆力、认知能力和正常运动逐渐丧失。多项研究表明转录失调是 HD 病理学的一个普遍特征，并表明突变蛋白 (Htt) 改变的组蛋白修饰可能有助于这一过程。然而，迄今为止，还没有对人类 HD 大脑中组蛋白修饰进行全基因组分析。这里提出的研究应用新颖的基因组技术来寻找 HD 大脑的表观遗传特征，目的是深入了解 HD 发病机制。我们的提案利用了两个独特的资源：（1）一种新颖的 FACS-ChIP-seq 方法，我们将应用该方法来建立和比较 HD 和对照大脑的神经元甲基化组； (2) HD 大脑的独特样本，包括一组与 CAG 重复扩展（范围 42-44 次重复）匹配的组，但发病年龄相差 30 年或更长时间。大脑的纹状体和皮质受累程度已得到广泛的神经病理学特征。由于我们发现 HD 大脑中的组蛋白 H3 甲基化标记与 CD4+ 细胞中的信号高度重叠，因此我们还将 HD 大脑中观察到的表观遗传特征改变与不同疾病阶段（症状前、早期和晚期 HD）的血液样本中的表观遗传特征进行比较因为这可能为 HD 血液提供一种新的表观遗传生物标志物。这些生物标志物对于评估药物治疗以重新调整破坏的基因表达具有转化意义。我们在六个 HD 前额皮质样本和 11 个正常对照中使用 FACS-ChIP-Seq 方法获得了初步数据，这为拟议研究的重要性提供了诱人的证据，并证明了我们应用这些技术和有意义地解释研究结果的能力。我们的方法代表了迄今为止针对组蛋白甲基化在 HD 发病机制中的作用的最全面的分析。无论结果如何，这些研究都将为 HD 发病机制的分子途径提供重要的新见解，并可能揭示 HD 治疗的新分子靶标。我们提出的鉴定和表征 HD 血细胞中独特的组蛋白甲基化生物标志物的建议增加了该建议的高转化影响。如果成功，这种生物标志物的鉴定将极大地促进新的 HD 疗法的临床试验，并提供一种新的方法来评估新的药物治疗是否可以纠正破坏的基因表达。