Translational regulation by covalent modification of mRNA

MRNA共价修饰对翻译的调节作用 项目摘要 衰老是一个复杂的过程，涉及因以下原因而导致的细胞功能随时间变化的丧失 基因组和表观遗传不稳定，翻译失调，细胞间通讯改变。 通过改变降解的表达，可以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 老鼠模型。对于许多令人信服的干预措施，减轻人类衰老相关疾病将 涉及(I)基因表达上调和/或(Ii)抑制难于用药或“不能用药” 蛋白质和配体。利用小分子增强蛋白质细胞活性并调节 非常规靶点的表达是药物发现中迫在眉睫的未满足的挑战。在……里面 在细胞的探索性工作中，我们一直观察到报告蛋白活性的显著增加 在与特定信使RNA(信使核糖核酸)结合并与其共价反应的配体存在的情况下。 通过对mRNA的共价修饰选择性地增加蛋白质的表达将是一个基础 抗衰老和RNA靶向治疗领域的进展。我们的发展研究 Proposal还将揭示细胞中信使核糖核酸修饰调节的基本机制 翻译。我们将探索蛋白质表达这一出乎意料和有趣的方面，以及它的 潜在的长期老龄化应用，通过以下两个目标：通过目标1，我们将优化 小分子介导的信使核糖核酸烷基化的翻译效应，通过目标2，我们将 建立小分子使信使核糖核酸烷基化上调的机制 编码蛋白的表达。

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.