Epigenetic-Genetic Modulations in Aging and Alzheimer's Disease Neurons

目前的建议是受到我们最近应用的全基因组分析方法的启发。 人脑神经元的染色质调控景观和遗传-表观遗传相互作用。我们假设 在衰老过程中，人类大脑皮层神经元中的活性染色质逐渐被修饰 染色体基因座。这些染色质修饰导致某些特定活性的表观遗传状态的改变 基因，导致易患阿尔茨海默病(AD)的大脑区域老化神经元的脆弱性- 相关的退化信号。我们计划识别这些衰老特定的神经染色质特征，标记为 针对活性基因启动子和活性基因增强子的修饰组蛋白。我们将采用CHIP-SEQ AD易感脑区神经元染色质全基因组分析技术 在按年龄分层的非痴呆者队列中和AD患者中都是如此。我们将搜索是否 在衰老和AD神经元中进行表观遗传修饰的一组基因在任何基因本体类别中都是丰富的，并且 特定的生物途径。具有改变的表观遗传特征的基因将进行进一步的测试，看看它们是否 与AD和AD相关性状的遗传风险基因座重叠。我们认为信号的基因 转导器，特别是具有应激反应和免疫功能的基因，是表观遗传学的目标。 衰老中的修饰-AD神经退行性变的基础神经元。这些预测将在动物身上得到验证。 通过一种新型的siRNA治疗化合物直接敲除基因活性来建立模型。

The current proposal was inspired by our recently applied methodology for whole-genome analysis of regulatory chromatin landscape and genetic-epigenetic interactions in human brain neurons. We hypothesize that, during aging, the active chromatin in human cortical neurons is gradually modified in a subset of chromosomal loci. These chromatin modifications lead to an altered epigenetic state of activity of certain genes, contributing to vulnerability of aging neurons in brain regions vulnerable to Alzheimer's disease (AD) - related degeneration signals. We plan to identify these aging-specific neuro-chromatin signatures marked by modified histones specific for active gene promoters and active gene enhancers. We will apply ChIP-seq technology for whole-genome analysis of neuronal chromatin extracted from brain regions susceptible to AD both in a cohort of non-demented individuals stratified by age and in AD patients. We will search whether the group of genes epigenetically modified in aging and AD neurons is enriched in any gene ontology category and specific biological pathway. The genes with altered epigenetic signatures will be tested further whether they overlap with the genetic risk loci for AD and AD-related traits. We suggest that the genes for signal transducers, especially for genes with stress-response and immune functions, are targets for epigenetic modifications in aging- neurons underlying AD neurodegeneration. These predictions will be tested in animal models by direct knockdown of gene activity by a novel type of siRNA therapeutic compounds.