Regulation of mRNA fate

mRNA命运的调控

• 批准号: 10318148
• 负责人: Jeremy Robert Sanford
• 金额: $ 37.14万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318148
• 关键词: Alternative Splicing; Biochemical; Code; Complex; Coupling; Cystic Fibrosis; Diabetes Mellitus; Diagnostic; Elements; Gene Expression; Genes; Genetic Transcription; Genome; Health; Human; Link; Malignant Neoplasms; Messenger RNA; Molecular; Pathway interactions; Polyribosomes; Problem Solving; Process; Protein Biosynthesis; Protein Isoforms; Proteins; RNA; RNA Processing; RNA Splicing; RNA, Messenger, Splicing; Regulation; Research; Spinal Muscular Atrophy; Technetium; Transcript; Translation Initiation; Translations; base; human disease; improved; messenger ribonucleoprotein; particle; programs

Abstract The process of alternative splicing (AS) is a powerful mechanism for generating mRNA diversity from protein coding genes. Alternative mRNA isoforms from the same gene can differ subtly from each other or have radical alterations in their sequence composition. Remarkably, very little is known about whether or not this diverse pool of mRNA is converted to protein. One intriguing clue for solving this problem comes from our recent studies suggesting that the process of alternative splicing influences the translational efficiency of the resultant mRNA isoforms. In this proposal, we use both biochemical and molecular approaches to untangle the intricate mechanisms coupling post-transcriptional gene expression. By determining how AS-TC elements reg- ulate mRNA translation we will be able to refute or support the central hypothesis of this proposal, that alterna- tively spliced transcripts are packaged into functionally distinct messenger ribonucleoprotein particles (mRNPs). If sequences associated with differential polyribosome association do not directly control translation initiation or elongation, then we will consider our alternative hypothesis: that a significant fraction of mRNA iso- form diversity arises from noisy splicing which are then excluded from polyribosomes by some unknown mRNA surveillance pathway. Solving this important problem will not only reveal how cis-elements influence transla- tional yield, but will also define mechanistic links between the processes of alternative splicing and mRNA translation. In the long-term, our research program will facilitate new opportunities for RNA-based diagnostics and therapies that will be applicable to a wide array of human diseases.

抽象的 替代剪接的过程（AS）是从 蛋白质编码基因。来自同一基因的替代mRNA同工型可以彼此微妙或 在其序列组成中具有根本改变。值得注意的是，关于是否知道是否 这种不同的mRNA池转化为蛋白质。解决这个问题的一个有趣的线索来自我们 最近的研究表明，替代剪接的过程影响 由此产生的mRNA同工型。在此提案中，我们使用生化和分子方法来解开 复杂的机制结合了转录后基因表达。通过确定AS-TC元素如何重新 ULATE mRNA翻译我们将能够驳斥或支持该提议的中心假设，即替代 将剪接的成绩单包装到功能上不同的墨核蛋白颗粒中 （mRNP）。如果与差分多核糖体关联相关的序列不能直接控制翻译 开始或伸长，我们将考虑我们的替代假设：很大一部分mRNA iso- 形式多样性是由嘈杂的剪接产生的 监视途径。解决这个重要问题不仅会揭示顺式元素如何影响转换 态产率，但还将定义替代剪接和mRNA的过程之间的机械联系 翻译。从长远来看，我们的研究计划将为基于RNA的诊断提供新的机会 以及适用于多种人类疾病的疗法。