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 转座元素（TES）是多产的遗传寄生虫，渗入> 45％的人类基因组，是 所有动物基因组的主要比例。衰老和疾病期间的激活会影响 神经元并改变动物活动。该假设很有吸引力，因为所有动物基因组都有主要 当动物年轻但在衰老和疾病期间被激活时，活跃TE的储层是潜在的。我们的 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。从根本上发现动物基因组之间的调节机制 在神经退行性疾病中，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。 该提议将通过处理小型处理调查如何调节衰老过程中的TE RNA如何调节 RNA通过天然RNAi途径。这项研究利用了我们实验室先前对TE的研究 果蝇衰老期间的调节，我们将对人类Te RNA的处理方式有了新的见解 在人类衰老期间成小的RNA，以及在患病状态下如何影响这些TE小RNA水平。这 最终目标将是检查在动物老化和中间如何影响TE RNA调节 神经退行性疾病，例如阿尔茨海默氏症，帕金森氏症和亨廷顿疾病。 该项目将在该项目中实现以下目标：目标1：破译染色质状态相关的状态 在果蝇和人类细胞中升高的TE表达升高；并测试调节的遗传干预措施 人类细胞和果蝇中TE的RNAi调节，其敲低和与与之相关的基因的突变 神经变性为了测量对疾病表型抑制和保存的反馈 染色质状态。目标2：在发育和衰老过程中确定小型RNA的范围； 并确定在神经退行性疾病中受影响的小RNA的范围。自从 该领域仍然缺乏对动物老化期间TE RNA处理事件的完全了解，我们的多 果蝇模型系统中的插脚遗传和基因组学方法将完成翻译 表征人类细胞和脑样品中TE RNA调节过程的目标。