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

年龄相关的表观遗传重复元件去抑制在阿尔茨海默病中的作用

• 批准号: 10537531
• 负责人: Alyssa Nicole Cavalier
• 金额: $ 3.87万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537531
• 关键词: ATAC-seq; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Automobile Driving; Bioinformatics; Biological; Biological Process; Biology; Biometry; Blood; Blood Cells; Brain; ChIP-seq; Chromatin; Chromatin Structure; Clinical Data; Clinical Research; Code; Colorado; Complementary DNA; Consult; DNA; DNA Methylation; DNA Transposable Elements; DNA methylation profiling; Data; Data Set; Development; Development Plans; Diagnosis; Double-Stranded RNA; Environment; Epigenetic Process; Family; Fluorescent in Situ Hybridization; Funding; Genes; Genetic Transcription; Genome; Genomic Segment; Goals; Heterochromatin; Histone Acetylation; Human; Human Genome; Immune; Immune signaling; Immunofluorescence Immunologic; Inflammation; Interferons; Junk DNA; Laboratories; Lead; Learning; Link; Mentors; Methods; Methylation; Molecular; Molecular Biology; Nerve Degeneration; Neurodegenerative Disorders; Patients; Play; Process; RNA; RNA Editing; Repetitive Sequence; Research; Research Personnel; Research Training; Risk Factors; Role; Sampling; Signal Transduction; Site; Source; Stimulator of Interferon Genes; Techniques; Training; Transcript; Translational Research; United States National Institutes of Health; Universities; Untranslated RNA; XCL1 gene; age related; aging brain; antiviral immunity; base; bisulfite sequencing; career; career development; chromatin modification; derepression; experience; familial Alzheimer disease; genome wide methylation; genome-wide; healthspan; insight; meetings; mild cognitive impairment; multiple omics; neuroinflammation; new therapeutic target; next generation sequencing; sensor; skills; symposium; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; translational scientist; whole genome

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.

项目摘要 年龄是零星（即与年龄相关的，不是遗传/家族性的）阿尔茨海默氏病（AD）的主要危险因素 神经炎症是大脑衰老和AD的关键驱动力。下一代的最新进展 测序（例如RNA-seq/转录组学）可能有助于确定与年龄/AD相关的神经炎症的原因； 但是，大多数衰老的转录组研究主要集中在编码基因上，而非编码 重复序列（代表人类基因组的50％）已在很大程度上被忽略。生长 我们实验室和其他实验室的证据表明，重复元素（re）成绩单的表达随着 年龄并可能有助于衰老/AD，但重新调节的确切机制是 不完全理解。一种可能性是表观遗传变化（这是 衰老/AD）可能涉及。这些表观遗传学变化如何导致转录本的积累尚不清楚， 但是有两种可能性：1）与年龄相关的染色质结构的变化和异染色质的丧失 （高度紧凑且无法访问）；或2）RES的DNA甲基化降低。这两个表观遗传学变化 可能会增加通常被抑制的RES的激活/表达，并且两者都可以代表新颖 治疗靶标。在此F31应用程序中，候选人Alyssa Cavalier，提议获得价值 翻译研究培训通过使用“多词学方法”来研究RE的表观遗传失调 笔录及其在衰老，神经炎症和AD中的作用。她将利用现有样本来 生成染色质的可及性和整个基因组甲基化测序数据，并使用生物信息学 分析以确定RES是否随衰老/AD的增加来自于表观遗传学的基因组区域 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术，翻译的科学家 研究脑衰老和神经退行性的生物学机制。骑士女士将在 科罗拉多州立大学（CSU）的最先进的环境与一支杰出的心理团队。这 赞助商汤姆·拉洛卡（Tom Larocca）博士拥有广泛的背景研究衰老和重新研究，并指导NIH资助 CSU的HealthSpan生物学实验室。咨询导师Drs。克里斯·林克（Chris Link），卡琳·汉密尔顿（Karyn Hamilton）和布莱恩（Brianne） Bettcher将提供有关从分子到临床研究的主题的专业知识，为Cavalier女士做准备 作为转化科学家的职业。骑士女士的职业发展计划包括：1） 临床数据的生物信息学，生物统计学和解释/分析； 2）学习最先进的湿lab 发展她的翻译研究技能的技术； 3）加强和扩大她的分子生物学 技能； 4）通过与她的心理团队互动进一步发展她的专业技能， 课程工作，每周实验室会议和科学会议。