DNA methylation in Alzheimer?s disease and normally aged brain

阿尔茨海默病和正常衰老大脑中的 DNA 甲基化

• 批准号: 8138180
• 负责人: PAUL D COLEMAN
• 金额: $ 10万
• 依托单位: BANNER SUN HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138180
• 关键词: Affect; Alzheimer' s Disease; Biology; Brain; Brain region; Cells; Cerebellum; DNA Methylation; Data; Disease Progression; Early Diagnosis; Gene Expression; Genes; Health; Immunohistochemistry; In Situ; Lead; Molecular; Neocortex; Research; Research Institute; Resources; Role; Site; The Sun; To specify; aging brain; case control; effective therapy; genome wide association study; molecular pathology; novel strategies; promoter; public health relevance

DESCRIPTION (provided by applicant): The proposed research represents the coordination of a number of existing facilities and resources aimed at defining the role(s) of DNA methylation in the molecular pathology of Alzheimer's disease. We will integrate the expertise of the Coleman/Rogers lab in Alzheimer's disease with the expertise of the Laird lab in DNA methylation to identify DNA methylation sites in a genome wide study of an affected (temporal neocortex) and a minimally affected (cerebellum) brain region of Alzheimer's disease (AD) and non demented control cases. The 550 brains to be utilized in this proposed study will come from the comprehensive and outstanding Brain Bank at Sun Health Research Institute. Since promoter DNA methylation only relates to the potential for gene expression, it may not be a very good predictor of gene expression differences. Consequently, we will determine the relationship between specific sites of DNA methylation and altered expression of specific genes in AD by correlating our DNA methylation data with an existing set of Affymetrix data on gene expression in ~100 normal and AD brains. Finally, to specify cell classes affected we will conduct combined immunohistochemistry and in situ htbridization studies to define cell classes affected by specific DNA methylation/expression changes. PUBLIC HEALTH RELEVANCE: A successful attack on Alzheimer's disease requires two components: 1) early diagnosis and 2) effective treatment that will significantly delay or halt disease progression. The genome wide study of DNA methylation in Alzheimer's disease proposed here will elucidate and extend the previously under appreciated role of a general molecular mechanism in the basic biology of AD and will lead to earlier diagnosis and new approaches to treatment of Alzheimer's disease.

描述（由申请人提供）：拟议的研究代表了一些现有设施和资源的协调，旨在确定DNA甲基化在阿尔茨海默病分子病理学中的作用。我们将整合科尔曼/罗杰斯实验室在阿尔茨海默病的专业知识与Laird实验室在DNA甲基化方面的专业知识，以确定在阿尔茨海默病（AD）和非痴呆对照病例的受影响（颞叶新皮层）和受影响最小（小脑）大脑区域的全基因组研究中的DNA甲基化位点。在这项拟议的研究中使用的550个大脑将来自太阳健康研究所的综合和优秀的大脑银行。由于启动子DNA甲基化仅与基因表达的潜力有关，因此它可能不是基因表达差异的非常好的预测因子。因此，我们将通过将我们的DNA甲基化数据与现有的一组关于~100个正常和AD大脑中基因表达的Affyphase数据相关联，来确定AD中DNA甲基化的特定位点与特定基因表达改变之间的关系。最后，为了确定受影响的细胞类别，我们将进行联合免疫组织化学和原位杂交研究，以确定受特定DNA甲基化/表达变化影响的细胞类别。公共卫生相关性：阿尔茨海默病的成功发作需要两个组成部分：1）早期诊断和2）有效的治疗，将显着延迟或停止疾病的进展。本文提出的阿尔茨海默病DNA甲基化的全基因组研究将阐明和扩展以前在AD基础生物学中的一般分子机制的作用，并将导致阿尔茨海默病的早期诊断和治疗的新方法。