Role of age-associated epigenetic repetitive element derepression in Alzheimer's Disease

项目总结 年龄是散发性(即与年龄相关，而不是遗传/家族性)阿尔茨海默病的主要危险因素， 神经炎症是大脑老化和阿尔茨海默病的关键驱动因素。下一代技术的最新进展 测序(例如，RNA序列/转录组)可能有助于确定与年龄/AD相关的神经炎的原因； 然而，大多数关于衰老的转录组研究主要集中在编码基因上，而非编码上 重复序列(占人类基因组的50%)在很大程度上被忽视了。生长 来自我们实验室和其他实验室的证据表明，重复元件(RE)转录本的表达随着 年龄和可能导致衰老/阿尔茨海默病，但发生稀土失调的确切机制是 不完全理解。一种可能性是表观遗传变化(这是 可能涉及衰老/AD)。这些表观遗传变化如何促进RE转录本的积累尚不清楚， 但有两种可能性：1)与年龄相关的染色质结构变化和异染色质丢失 (高度紧凑和难以接近)；或2)RES的DNA甲基化减少。这两种表观遗传变化 可以增加通常被抑制的RES的激活/表达，两者都可能代表新的 治疗靶点。在这个F31应用程序中，候选人Alyssa Cavalier提议获得有价值的 运用“多组学方法”进行翻译研究训练以研究稀土的表观遗传失调 转录及其在衰老、神经炎症和阿尔茨海默病中的作用。她将利用现有的样本来 产生染色质可及性和全基因组甲基化测序数据，并使用生物信息学 分析以确定RES是否随年龄增加/AD起源于显示表观遗传的基因组区域 监管失调。她的直接目标是获得必要的基本经验和专业技能 进行独立研究。她的长期目标是成为一名学院派的翻译科学家 研究脑老化和神经退行性变的生物学机制。Cavalier女士将在一家 科罗拉多州立大学(CSU)拥有卓越的指导团队，提供最先进的环境。这个 赞助商Tom LaRocca博士具有广泛的老龄化和RE研究背景，并领导着NIH资助的 科罗拉多州立大学健康生物实验室。咨询导师克里斯·林克博士、卡琳·汉密尔顿博士和布里安 Bettcher将提供从分子到临床研究的专业知识，为Cavalier女士做好准备 翻译科学家的职业生涯。Cavalier女士的职业发展计划包括：1)培训 生物信息学、生物统计学和临床数据的解释/分析；2)学习最先进的湿法实验室 培养她的翻译研究技能的技巧；3)加强和拓宽她的分子生物学 技能集；以及4)通过与指导团队的互动进一步发展她的专业技能， 课程作业、每周实验室会议和科学会议。

PROJECT SUMMARY Age is the primary risk factor for sporadic (i.e., age-related, not genetic/familial) Alzheimer’s disease (AD), and neuroinflammation is a key driver of brain aging and AD. Recent advances in next-generation sequencing (e.g., RNA-seq/transcriptomics) may help to identify causes of age/AD-related neuroinflammation; however, most transcriptome studies of aging have largely focused on coding genes, while non-coding repetitive sequences (which represent >50% of the human genome) have been largely ignored. Growing evidence from our lab and others shows that expression of repetitive element (RE) transcripts increases with age and may contribute to aging/AD, but the exact mechanisms by which RE dysregulation occurs are incompletely understood. One possibility is that epigenetic changes (which are an established feature of aging/AD) may be involved. How these epigenetic changes contribute to RE transcript accumulation is unclear, but there are two possibilities: 1) age-associated changes in chromatin structure and loss of heterochromatin (highly compact and inaccessible); or 2) reduced DNA methylation of REs. Both of these epigenetic changes could increase activation/expression of REs that are normally suppressed, and both could represent novel therapeutic targets. In this F31 application, the candidate, Alyssa Cavalier, proposes to gain valuable translational research training by using a “multi-omics approach” to study epigenetic dysregulation of RE transcripts and their role in aging, neuroinflammation and AD. She will take advantage of existing samples to generate chromatin accessibility and whole genome methylation sequencing data, and use bioinformatics analyses to determine if REs increased with aging/AD originate from genomic regions that show epigenetic dysregulation. Her immediate goal is to gain the fundamental experience and professional skills necessary to perform independent research. Her long-term goal is to become an academic, translational scientist investigating the biological mechanisms of brain aging and neurodegeneration. Ms. Cavalier will train in a state-of-the-art environment with an exceptional mentoring team at Colorado State University (CSU). The sponsor, Dr. Tom LaRocca, has an extensive background studying aging and RE, and directs the NIH-funded Healthspan Biology Laboratory at CSU. Consulting mentors Drs. Chris Link, Karyn Hamilton, and Brianne Bettcher will provide expertise on topics ranging from molecular to clinical research to prepare Ms. Cavalier for a career as a translational scientist. Ms. Cavalier’s career development plan consists of: 1) training in bioinformatics, biostatistics and interpretation/analyses of clinical data; 2) learning state-of-the-art wet-lab techniques to develop her translational research skills; 3) strengthening and broadening her molecular biology skillset; and 4) further developing her professional skills through interaction with her mentoring team, coursework, weekly lab meetings, and scientific conferences.