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

衰老和阿尔茨海默病神经元的表观遗传-遗传调节

• 批准号: 9910352
• 负责人: EVGENY I ROGAEV
• 金额: $ 65.03万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910352
• 关键词: 3xTg-AD mouse; Adult; Age; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Animal Model; Atrophic; Biological; Brain; Brain region; Categories; Cell Nucleus; Cerebrum; ChIP-seq; Chromatin; Chronic stress; Code; Craniocerebral Trauma; Data; Elderly; Enhancers; Epigenetic Process; Gene Mutation; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genomic Segment; Heterogeneity; Histones; Human; Impaired cognition; Impairment; Individual; Late Onset Alzheimer Disease; Lead; Link; Location; Maps; Mental Depression; Methodology; Modification; Molecular; Mus; Nerve Degeneration; Neuroglia; Neurons; Ontology; Pathology; Pathway interactions; Post-Traumatic Stress Disorders; Regulation; Risk; Risk Factors; Role; Signal Transduction; Stress; System; Technology; Testing; Transducers; Transgenic Model; Traumatic Brain Injury; Untranslated RNA; abeta accumulation; behavioral impairment; biological adaptation to stress; biological systems; brain tissue; chromatin modification; cohort; comparative; cortex mapping; design; endophenotype; gene repression; genetic analysis; genetic signature; genetic variant; genome analysis; glucocorticoid-induced orphan receptor; human subject; immune function; innovation; knock-down; middle age; non-demented; novel; promoter; relating to nervous system; risk variant; tau Proteins; therapeutic siRNA; trait; transcriptome; whole genome

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.

当前提案的灵感来自于我们最近应用的全基因组分析方法 人脑神经元的调节染色质景观和遗传-表观遗传相互作用。我们假设 在衰老过程中，人类皮质神经元中的活性染色质的一部分逐渐发生改变 染色体位点。这些染色质修饰导致某些特定活性的表观遗传状态发生改变 基因，导致易患阿尔茨海默病 (AD) 的大脑区域中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异性神经染色质特征 修饰组蛋白特异性针对活性基因启动子和活性基因增强子。我们将应用 ChIP-seq 对从易患 AD 的大脑区域中提取的神经元染色质进行全基因组分析的技术 既包括按年龄分层的非痴呆个体队列，也包括 AD 患者。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丰富于任何基因本体论类别，并且 特定的生物学途径。将进一步测试具有改变的表观遗传特征的基因是否 与 AD 和 AD 相关性状的遗传风险位点重叠。我们建议信号基因 转导子，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 AD 神经变性背后的衰老神经元的改变。这些预测将在动物身上进行测试 通过一种新型的 siRNA 治疗化合物直接敲低基因活性来建立模型。