Transposable Element (TE) RNA regulation via small RNA pathways in aging cells and neurodegeneration.

转座元件 (TE) RNA 通过小 RNA 途径对衰老细胞和神经退行性疾病进行调节。

• 批准号: 10518546
• 负责人: NELSON C LAU
• 金额: $ 70.33万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518546
• 关键词: ATAC-seq; Adolescent; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Animals; Atlases; Biochemical; Biological; Biological Models; Brain; Brain region; Cell Aging; Cells; Chromatin; Complement; DNA Sequence Alteration; DNA Transposable Elements; Data Set; Development; Disease; Drosophila genus; Event; Feedback; Functional disorder; Gene Mutation; Genetic; Genetic Transcription; Genome; Genome Stability; Genomic approach; Genomics; Goals; Heterochromatin; Human; Human Cell Line; Human Genome; Huntington Disease; Individual; Infant; Investigation; Lead; Link; Maps; Measures; MicroRNAs; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parasites; Parkinson Disease; Pathway interactions; Patients; Pattern; Process; RNA; RNA Interference; RNA Interference Pathway; RNA Processing; Regulation; Retrotransposon; Sampling; Small RNA; System; Testing; Transcript; Transgenic Organisms; aged; cohort; disease phenotype; frontal lobe; gene therapy; genetic approach; genetic testing; genome-wide; genomic RNA; insight; juvenile animal; knock-down; preservation; protein TDP-43; tau expression; transcriptome; transcriptomics; translational study

Project Summary/Abstract Transposable elements (TEs) are prolific genetic parasites infiltrating >45% of the human genome and are major proportions of all animal genomes. TE activation during aging and disease affects the transcriptomes of neurons and alter animal activity. This hypothesis is attractive because all animal genomes harbor a major reservoir of active TEs that are latent when animals are young but are activated during aging and disease. Our lab studies how the natural RNA interference (RNAi) system recognizes and silences TE transcripts to preserve genome stability. To fundamentally uncover the regulatory mechanisms between animal genomes and TEs in neurodegenerative disorders, we are deploying genetics, genomics, biochemical and small RNA analytical approaches on the RNAi pathway. This proposal will investigate how TE RNAs activated during aging are regulated by processing into small RNAs via natural RNAi pathways. This study leverages our lab’s previously established investigations of TE regulation during Drosophila aging, and we will bring new insight into how human TE RNAs are also processed into small RNAs during human aging and how these TE small RNA levels are affected in diseased states. The ultimate goal will be to examine how TE RNA regulation is affected during animal aging and in neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. This project will achieve the following aims in this project: Aim 1: Decipher the chromatin states associated with elevated TE expression in aging Drosophila and human cells; and test genetic interventions that modulate RNAi regulation of TEs in human cells and Drosophila with knockdowns and mutations of genes linked to neurodegeneration in order to measure the feedback to disease phenotype suppression and preserving chromatin states. Aim 2: Determine the range of human brain TE small RNAs during development and aging; and determine the range of human brain TE small RNAs being affected in neurodegenerative diseases. Since the field still lacks a complete understanding of TE RNA processing events during animal aging, our multi- prong genetic and genomics approach in the Drosophila model system will complement the translational objectives of characterizing the TE RNA regulation process in human cells and brain samples.

项目概要/摘要 转座元件 (TE) 是一种多产的遗传寄生虫，渗透到人类基因组的 45% 以上，并且 所有动物基因组的主要部分在衰老和疾病过程中会影响转录组。 这个假设很有吸引力，因为所有动物基因组都含有一个主要的基因组。 活性 TE 的储存库在动物年轻时处于潜伏状态，但在衰老和疾病期间被激活。 实验室研究天然 RNA 干扰 (RNAi) 系统如何识别和沉默 TE 转录本 保持基因组稳定性。从根本上揭示动物基因组之间的调控机制。 和神经退行性疾病中的 TE，我们正在部署遗传学、基因组学、生化和小 RNA RNAi 途径的分析方法。 该提案将研究衰老过程中激活的 TE RNA 如何通过加工成小分子来调节 通过天然 RNAi 途径的 RNA 本研究利用了我们实验室之前对 TE 进行的研究。 果蝇衰老过程中的调控，我们将为人类 TE RNA 的加工方式带来新的见解 人类衰老过程中 TE 小 RNA 的转化，以及这些 TE 小 RNA 水平在疾病状态下如何受到影响。 最终目标是研究 TE RNA 调节在动物衰老和衰老过程中如何受到影响。 神经退行性疾病，例如阿尔茨海默病、帕金森病和亨廷顿病。 该项目将实现以下目标： 目标 1：破译相关染色质状态 老化果蝇和人类细胞中 TE 表达升高；并测试调节的遗传干预措施 RNAi 对人类细胞和果蝇中 TE 的调控，通过敲除和突变相关基因 神经变性，以测量对疾病表型抑制和保存的反馈 目标 2：确定人脑 TE 小 RNA 在发育和衰老过程中的范围； 并确定人脑 TE 小 RNA 在神经退行性疾病中受到影响的范围。 该领域仍然缺乏对动物衰老过程中 TE RNA 加工事件的完整了解，我们的多 果蝇模型系统中的叉遗传学和基因组学方法将补充转化 表征人类细胞和大脑样本中 TE RNA 调节过程的目标。