DNA methylation in Alzheimer?s disease and normally aged brain

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(S)。我们将整合Coleman/Rogers实验室在阿尔茨海默病方面的专业知识和Laird实验室在DNA甲基化方面的专业知识，以在阿尔茨海默病(AD)和非痴呆对照病例的全基因组研究中确定DNA甲基化位置，研究对象是阿尔茨海默病(AD)和非痴呆对照病例的受累(颞叶新皮质)和受影响最小的(小脑)大脑区域。这项拟议中的研究将使用550个大脑，这些大脑将来自太阳健康研究所全面而杰出的脑库。由于启动子DNA甲基化只与基因表达的潜力有关，它可能不是一个很好的预测基因表达差异的指标。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约100个正常和AD大脑中基因表达的Affymetrix数据相关联，来确定特定DNA甲基化位点与AD中特定基因表达变化之间的关系。最后，为了确定受影响的细胞类别，我们将进行免疫组织化学和原位杂交相结合的研究，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：成功治疗阿尔茨海默病需要两个组成部分：1)早期诊断和2)有效的治疗将显著延缓或阻止疾病的进展。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先前被低估的一般分子机制在AD基础生物学中的作用，并将导致阿尔茨海默病的早期诊断和新的治疗方法。

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.