Translational regulation by covalent modification of mRNA

通过 mRNA 共价修饰进行翻译调控

• 批准号: 10789242
• 负责人: Kevin M Weeks
• 金额: $ 42.57万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-09-19
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10789242
• 关键词: Address; Aging; Alkylating Agents; Alkylation; Binding; Biological Assay; Cell Aging; Cell physiology; Cells; Chemicals; Collaborations; Complex; Data; Development; Disease; Disease model; Engineering; Epigenetic Process; Gene Expression Regulation; Genes; Genomics; Goals; High-Throughput Nucleotide Sequencing; Human; Incubated; Intervention; Laboratories; Ligand Binding; Ligands; Longevity; Measures; Mediating; Messenger RNA; Modification; Molecular Chaperones; Monitor; Mutation; Outcome Study; Pharmaceutical Preparations; Positioning Attribute; Prevention; Process; Production; Proteins; RNA; RNA Binding; RNA Sequences; RNA-targeting therapy; Reaction; Regulation; Reporter; Research Proposals; Science; Signaling Molecule; Site; Structure; Structure-Activity Relationship; System; Technology; Testing; Therapeutic; Time; Translating; Translational Regulation; Translations; Up-Regulation; Work; adduct; analog; anti aging; cellular engineering; design; disability; drug discovery; experimental study; gene therapy; innovation; intercellular communication; mouse model; overexpression; prevent; protein expression; protein function; small molecule; structural biology; transcription factor; translational impact

Translational regulation by covalent modification of mRNA Project Summary Aging is a complex process that involves time-dependent loss of cellular functions resulting from genomic and epigenetic instability, translational dysregulation, and altered intercellular communication. Increased longevity and healthier lifespan can be promoted by altering expression of degradation- related proteins, transcription factors, chaperones, and signaling molecules in cellular systems and mouse models. For many compelling interventions, mitigating aging-related diseases in humans will involve (i) upregulation of gene expression and/or (ii) inhibition of hard-to-drug or "undruggable" proteins and ligands. Increasing protein cellular activity using small molecules and modulating the expression of non-conventional targets are compelling unmet challenges in drug discovery. In exploratory work in cells, we have consistently observed significant increases in reporter protein activity in the presence of ligands that bind to and covalently react with a specific messenger RNA (mRNA). Selective increases in protein expression by covalent modifications of mRNA would be a foundational advance for the fields of anti-aging and RNA-targeted therapeutics. The developmental studies we propose will also reveal fundamental mechanisms by which mRNA modifications in cells modulate translation. We will explore this unanticipated and intriguing aspect of protein expression, and its potential longer-term applications to aging, via the following two Aims: Through Aim 1, we will optimize the translational effect of small molecule-mediated mRNA alkylation, and, through Aim 2, we will establish the mechanism through which alkylation of an mRNA by a small molecule upregulates expression of the encoded protein.

mRNA共价修饰的翻译调控 项目摘要 衰老是一个复杂的过程，涉及细胞功能的时间依赖性丧失， 基因组和表观遗传不稳定性、翻译失调和改变的细胞间通讯。 延长寿命和更健康的寿命可以通过改变降解的表达来促进- 相关的蛋白质，转录因子，分子伴侣和细胞系统中的信号分子， 小鼠模型。对于许多引人注目的干预措施，减轻人类与衰老有关的疾病将 涉及（i）基因表达上调和/或（ii）难以用药或“不可用药”的 蛋白质和配体。使用小分子增加蛋白质细胞活性并调节蛋白质细胞活性。 非常规靶标的表达是药物发现中令人信服的未解决的挑战。在 在细胞中的探索性工作中，我们一直观察到报告蛋白活性的显著增加 在配体的存在下，所述配体与特定信使RNA（mRNA）结合并共价反应。 通过mRNA的共价修饰选择性增加蛋白质表达将是一个基础 在抗衰老和RNA靶向治疗领域取得进展。发展研究，我们 这项研究还将揭示细胞中mRNA修饰调节 翻译.我们将探讨蛋白质表达的这一意想不到的和有趣的方面， 潜在的长期应用老化，通过以下两个目标：通过目标1，我们将优化 小分子介导的mRNA烷基化的翻译效应，并通过目标2，我们将 建立小分子对mRNA的烷基化上调的机制 编码蛋白质的表达。