Systems-wide analysis of oxidative stress-responsive m6A epitranscriptome

氧化应激反应 m6A 表观转录组的全系统分析

• 批准号: 10375555
• 负责人: Yi-Lan Weng
• 金额: $ 40.23万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375555
• 关键词: 3' Untranslated Regions; Address; Axon; Biological Markers; Biological Process; Catalytic Domain; Cells; Characteristics; Complex; Data; Dependence; Development; Diagnostic; Disease; Embryo; Environmental Exposure; Etiology; Exposure to; Health; Hela Cells; Human; Investigation; Kidney; Length; Link; Literature; Mass Spectrum Analysis; Mediating; Mental disorders; Metabolism; Methodology; Methods; Methylation; Methyltransferase; Modification; Molecular; Nervous System control; Neurodegenerative Disorders; Neurons; Oxidative Stress; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Pattern; Physiological; Play; Predisposition; Prevention strategy; Process; Protein Isoforms; RNA; RNA Transport; Regulation; Regulatory Element; Research; Risk; Role; Signaling Molecule; Specific qualifier value; Stimulus; Stress; Synapses; System; To specify; Toxic Environmental Substances; Toxicant exposure; Transcript; Validation; Work; adverse outcome; base; biological adaptation to stress; biomarker identification; design; disorder risk; epitranscriptome; epitranscriptomics; gene environment interaction; genome-wide; human disease; innovation; insight; interest; methylation pattern; nervous system disorder; novel; protein TDP-43; response; sodium arsenite; toxicant; transcriptome; treatment strategy

PROJECT SUMMARY/ABSTRACT The recent emergence of the epitranscriptomics field has opened the possibility to understand and manipulate a previously underappreciated regulatory layer involved in biological processes. In particular, our research focuses on m6A as a candidate of interest given that it is the most prevalent RNA modification in the nervous system that controls multiple aspects of RNA metabolism. We have previously shown the critical roles of m6A regulation in axonal plasticity and synaptic activity. This proposal extends our research scope and focuses on how the m6A epitranscriptome responds to environmental perturbation using innovative methods for the identification of biomarkers and molecular pathways linked to adverse outcomes. We will use system-wide approaches to address the following questions: (i) What is the mechanism to remodel the m6A epitranscriptome upon toxicant exposure, (ii) How do the dynamics of m6A reshape the transcriptome? (iii) What are the characteristics of mis-localized RNA that are associated with disease state and risk? We expect that our proposed study will significantly advance our understanding of how epitranscriptomic regulatory processes constitute key pathogenic mechanisms following environmental challenges. Data gained from our systematic profiling and functional validation may offer new opportunities for developing diagnostics and/or biomarkers to facilitate the development of more effective prevention and treatment strategies for these diseases.

项目摘要/摘要 最近表位转录组学领域的出现为理解和操纵提供了可能 生物过程中涉及的一个以前被低估的监管层。特别是，我们的研究 重点关注m6A作为一个感兴趣的候选，因为它是神经中最流行的RNA修饰 控制RNA代谢的多个方面的系统。我们之前已经展示了M6A的关键作用 轴突可塑性和突触活动的调节。这一建议扩大了我们的研究范围，并将重点放在 M6A表位转录组如何使用创新的方法对环境扰动做出反应 识别与不良结果相关的生物标记物和分子途径。我们将在系统范围内使用 解决以下问题的方法：(一)重塑m6A表位转录组的机制是什么 在毒物暴露后，(Ii)m6A的动态如何重塑转录组？(Iii)什么是 与疾病状态和风险相关的错误定位的RNA的特征？我们希望我们的 拟议的研究将显著提高我们对表位转录调控过程的理解 构成环境挑战后的关键致病机制。从我们的系统中获得的数据 简档分析和功能验证可以为开发诊断和/或生物标志物提供新的机会 促进为这些疾病制定更有效的预防和治疗战略。