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.

通过 mRNA 共价修饰进行翻译调控 项目概要 衰老是一个复杂的过程，涉及随时间变化而导致的细胞功能丧失 基因组和表观遗传不稳定、翻译失调和细胞间通讯改变。 通过改变降解的表达可以促进延长寿命和更健康的寿命 细胞系统中的相关蛋白质、转录因子、伴侣和信号分子 鼠标模型。对于许多引人注目的干预措施来说，减轻人类与衰老相关的疾病将 涉及（i）基因表达的上调和/或（ii）难以成药或“不可成药”的抑制 蛋白质和配体。使用小分子增加蛋白质细胞活性并调节 非常规靶标的表达是药物发现中尚未解决的重大挑战。在 在细胞的探索性工作中，我们一直观察到报告蛋白活性显着增加 在存在与特定信使 RNA (mRNA) 结合并共价反应的配体的情况下。 通过 mRNA 的共价修饰选择性增加蛋白质表达将是一个基础 抗衰老和RNA靶向治疗领域取得进展。我们的发展研究 提议还将揭示细胞中 mRNA 修饰调节的基本机制 翻译。我们将探索蛋白质表达的这个意想不到且有趣的方面，及其 通过以下两个目标，我们将在衰老方面发挥潜在的长期应用：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，并且通过目标 2，我们将 建立小分子对 mRNA 的烷基化上调的机制 编码蛋白的表达。