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: 10701082
• 负责人: NELSON C LAU
• 金额: $ 71.21万
• 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/10701082
• 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 Mappings; Genome Stability; Genomic approach; Genomics; Goals; Heterochromatin; Human; Human Cell Line; Human Genome; Huntington Disease; Individual; Infant; Infiltration; Investigation; Link; 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; new technology; posttranscriptional; 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.

项目摘要/摘要 转座元件(TES)是一种大量的遗传寄生虫，渗透到人类基因组的45%，是 所有动物基因组的主要比例。TE在衰老和疾病过程中的激活影响转录 神经元和改变动物活动。这一假说之所以吸引人，是因为所有动物的基因组都含有一个主要的 动物幼年时潜伏，但在衰老和疾病期间被激活的活跃TE的蓄水池。我们的 实验室研究自然RNA干扰(RNAi)系统如何识别和沉默TE转录本 保持基因组的稳定性。从根本上揭示动物基因组之间的调控机制 在神经退行性疾病中，我们正在运用遗传学、基因组学、生化和小RNA RNAi途径的分析方法。 这项提案将调查在老化过程中激活的TE RNA是如何通过将其加工成小分子来调节的 通过自然的RNAi途径。这项研究利用了我们实验室先前建立的对TE的调查 在果蝇衰老过程中的调控，我们将为人类TE RNA也是如何处理的提供新的见解 在人类衰老过程中转化为小RNA，以及这些小RNA水平在疾病状态下是如何受到影响的。这个 最终目标将是研究在动物衰老过程中和在 神经退行性疾病，如阿尔茨海默氏症、帕金森氏症和亨廷顿病。 本项目将实现以下目标：目标1：破译相关的染色质状态 在衰老的果蝇和人类细胞中TE表达增加；并测试调节 基因敲除和突变对人细胞和果蝇TES的RNAi调控 为了测量神经退行性变对疾病表型抑制和保存的反馈 染色质状态。目的2：确定人脑发育和衰老过程中小RNA的表达范围； 并确定在神经退行性疾病中受影响的人脑TE小RNA的范围。自.以来 该领域仍然缺乏对动物衰老过程中的TE RNA加工事件的完整了解，我们的多个 果蝇模型系统中的分支遗传和基因组学方法将补充翻译 目的：描述人类细胞和大脑样本中的te RNA调控过程。