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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

项目摘要

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.

项目概要年龄是散发性（即与年龄相关，而非遗传/家族性）阿尔茨海默病 (AD) 的主要危险因素，神经炎症是大脑衰老和 AD 的关键驱动因素。测序（例如 RNA-seq/转录组学）可能有助于确定年龄/AD 相关神经炎症的原因；然而，大多数衰老转录组研究主要集中在编码基因，而非编码基因重复序列（占人类基因组的 50% 以上）在很大程度上被忽视了。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，可能会导致衰老/AD，但 RE 失调发生的确切机制是一种可能性是表观遗传变化（这是一个既定的特征）。这些表观遗传变化如何促进 RE 转录物积累尚不清楚，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（高度紧凑且难以接近）；或 2) RE 的 DNA 甲基化减少。可以增加通常被抑制的 RE 的激活/表达，并且两者都可以代表新的在这个 F31 申请中，候选人 Alyssa Cavalier 提出获得有价值的收益。使用“多组学方法”研究 RE 表观遗传失调的转化研究培训她将利用现有样本来研究转录本及其在衰老、神经炎症和 AD 中的作用。生成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 RE 是否随着衰老/AD 的增加源自显示表观遗传的基因组区域她的近期目标是获得必要的基本经验和专业技能。她的长期目标是成为一名学术转化科学家。卡瓦利尔女士将在一项研究中研究大脑衰老和神经退行性变的生物学机制。科罗拉多州立大学 (CSU) 拥有最先进的环境和卓越的指导团队。发起人 Tom LaRocca 博士在衰老和 RE 方面拥有广泛的背景，并领导 NIH 资助的项目科罗拉多州立大学 Healthspan 生物学实验室咨询导师 Chris Link、Karyn Hamilton 和 Brianne 博士。 Bettcher 将提供从分子到临床研究等主题的专业知识，帮助 Cavalier 女士做好准备 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) 学习最先进的湿实验室培养她的转化研究技能的技术；3）加强和拓宽她的分子生物学； 4）通过与导师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。