The role of Sirtuins in neurodegenerative disease

Sirtuins 在神经退行性疾病中的作用

• 批准号: 10350151
• 负责人: Jason Glen Wood
• 金额: $ 26.59万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2021-08-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350151
• 关键词: role; Sirtuins; neurodegenerative; disease

This proposal seeks to characterize the transcriptome and epigenome of models of Alzheimer’s disease (AD) in Drosophila melanogaster. The project further proposes to investigate the role of sirtuins in the development and progression of AD, and to understand the molecular mechanism of their reported neuroprotective effects. We will use a computational biology approach with a combination of next-generation sequencing-based techniques to identify both transcriptional and chromatin state changes that take place during AD and determine how these are modified by overexpression or knockout of sirtuin proteins. The specific aims of this project seek to explore the hypothesis that AD is characterized by a loss of heterochromatin, increased genomic instability, and aberrant transcription, and that sirtuin overexpression can stabilize these processes and delay disease progression. This hypothesis is based on several recent studies linking aspects of sirtuin biology to neurodegenerative disease. Aim 1 will determine how modulating sirtuin expression affects the transcriptional profile of fly AD models. We will use an RNA-seq approach to study gene expression, small RNA species, and transposable element expression in AD models, and observe how these are affected upon overexpression or knockout of Sirt6 and Sirt1. Aim 2 will explore how modulating sirtuin expression affects the chromatin landscape of fly AD models. Specifically, we will determine chromatin accessibility using ATAC-seq, and determine the pattern and abundance of histone marks known to be targeted by sirtuins, including H3K9ac, H3K56ac, and H4K16ac by ChIP-seq. We will also determine how these AD chromatin profiles are affected by overexpressing or knocking out sirtuins. These experiments will generate rich and comprehensive data sets, analysis of which will yield insights into both sirtuin biology and Alzheimer’s disease etiology and progression. We also expect to leverage the strengths of the Drosophila model system, including cost, time, and precise control of gene expression, to validate computational biology observations in vivo and follow up with traditional genetic experiments.

该提案旨在表征阿尔茨海默病（AD）模型的转录组和表观基因组， 果蝇该项目进一步建议调查sirtuins在发展中的作用， AD的进展，并了解其报告的神经保护作用的分子机制。我们将使用 一种结合下一代测序技术的计算生物学方法， 转录和染色质状态的变化发生在AD，并决定如何修改这些 过表达或敲除沉默调节蛋白。 本项目的具体目标是探索AD的特征是异染色质丢失的假设， 增加的基因组不稳定性和异常转录，而沉默调节蛋白过表达可以稳定这些过程 并延缓疾病进展。这一假设是基于最近的几项研究，这些研究将sirtuin生物学的各个方面与 神经退行性疾病目的1将确定调节沉默调节蛋白表达如何影响转录谱 飞AD模型。我们将使用RNA-seq方法来研究基因表达，小RNA种类和转座 元件表达，并观察这些如何影响Sirt 6的过表达或敲除， Sirt1.目标2将探索调节沉默调节蛋白表达如何影响苍蝇AD模型的染色质景观。 具体来说，我们将使用ATAC-seq确定染色质可及性，并确定染色质的模式和丰度。 已知由sirtuins靶向的组蛋白标记，包括ChIP-seq的H3 K9 ac、H3 K56 ac和H4 K16 ac。我们还将 确定过表达或敲除sirtuins如何影响这些AD染色质谱。 这些实验将产生丰富而全面的数据集，对这些数据集的分析将有助于深入了解这两个方面。 sirtuin生物学与阿尔茨海默病的病因和进展。我们还希望利用 果蝇模型系统，包括成本，时间，和精确控制基因表达，以验证计算 活体生物学观察和传统遗传学实验的后续研究。