Role of miRNA Argonautes in organismal aging

miRNA Argonautes 在机体衰老中的作用

• 批准号: 9920648
• 负责人: AMY E. PASQUINELLI
• 金额: $ 37.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920648
• 关键词: Adult; Age of Onset; Aging; Amino Acids; Animals; Binding; Biological; Caenorhabditis elegans; Code; Complex; Data; Data Set; Development; Disease; Exhibits; Foundations; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Guide RNA; Heart; Human Biology; IGF-1 Signaling Pathway; Individual; Insulin; Insulin-Like Growth Factor I; Intention; Intestines; Knowledge; Lead; Life; Link; Longevity; Longevity Pathway; Malignant Neoplasms; Maps; Measures; Messenger RNA; Methodology; Methods; MicroRNAs; Molecular; Neurons; Organism; Pathology; Pathway interactions; Pattern; Phenotype; Plants; Play; Post-Transcriptional Regulation; Process; Proteins; RNA; Regulation; Regulator Genes; Regulatory Element; Regulatory Pathway; Role; Signal Transduction; Site; Small RNA; Stretching; System; Testing; Tissues; Transcript; Work; age related; cell type; design; experimental study; healthspan; human disease; innovation; insight; mRNA Expression; mature animal; mutant; nervous system disorder; neuronal cell body; novel; paralogous gene; prevent; recruit

PROJECT SUMMARY The discovery that regulatory RNAs control almost every biological pathway has revolutionized our understanding of gene expression over the past decade. At the forefront, microRNAs (miRNAs) have proven to be an abundant and essential class of RNA molecules in plants and animals. The importance of miRNAs in human biology is highlighted by the increasing recognition that misregulation of specific miRNA pathways contributes to complex diseases, including cancer, heart ailments and neuronal pathologies. MiRNAs depend on Argonaute (AGO) proteins to bind and regulate the expression of target genes at the post-transcriptional level. In C. elegans, the AGO Like Genes 1 and 2 (ALG-1, ALG-2) proteins are over 85% identical at the amino acid level and function redundantly during development. However, at adulthood these AGOs take on opposing roles, as alg- 1 or alg-2 mutants exhibit shortened or extended lifespans, respectively. Additionally, healthspan, as measured by maximum velocity, is reduced in alg-1 and increased in alg-2 mutants compared to wildtype adults. One longevity pathway that is differentially impacted by the loss of either AGO is Insulin/ IGF-1 Signaling (IIS). These preliminary studies lead to the hypothesis that differences in the expression or activity of alg-1 and alg-2 allow them to regulate distinct sets of genes in the IIS pathway to control lifespan in adult animals. In Aims 1 and 2, the genetic basis and potential tissue specific activities responsible for the opposing longevity functions of alg-1 and alg-2 will be determined. Cutting edge methods for detecting the specific miRNAs and targets bound by ALG-1 and ALG-2 will be utilized in Aim 3. This will result in the first map of miRNA specific target sites in an adult animal and provide unprecedented insights into the direct roles of alg-1 and alg-2 in the IIS, and perhaps other, longevity pathways. Furthermore, by revealing the miRNA targeting landscape in adult C. elegans a new foundation will be set for investigating longevity roles for conserved miRNAs and targets in other species. Another broad impact of this study is that it will reveal how two proteins considered redundant take on opposing roles in aging, which will provide a paradigm for considering the importance of context for the function of related genes in any pathway. Additionally, the methods used here to identify miRNA specific target sites are generally applicable across systems and, thus, will help eliminate a longstanding barrier to matching miRNAs with their endogenous target sites. Finally, a long-term goal of this work is to contribute to the rational design of strategies to modify gene expression with the intention of preventing or counteracting age-related maladies.

项目摘要 调节性RNA控制几乎所有生物途径的发现彻底改变了我们的研究。 在过去的十年里，基因表达的理解。在最前沿，microRNAs（miRNAs） 被证明是植物和动物中丰富和必需的一类RNA分子。的 越来越多的人认识到miRNA在人类生物学中的重要性， 特定的miRNA通路的错误调节导致复杂的疾病，包括癌症、心脏病、 疾病和神经病理。miRNA依赖于Argonaute（AGO）蛋白结合， 在转录后水平调节靶基因的表达。In C. elegans，the AGO Like 基因1和2（ALG-1、ALG-2）蛋白在氨基酸水平和功能上超过85%相同 在发展过程中。然而，在成年期，这些AGO承担相反的角色，如Alg- 1或alg-2突变体分别表现出寿命缩短或延长。此外，healthspan作为 通过最大速度测量，与对照组相比，在alg-1中降低，在alg-2突变体中增加。 野生型成年人一个寿命途径，是不同的影响，无论是AGO的损失是 胰岛素/ IGF-1信号转导（IIS）。这些初步研究导致了一个假设，即在 alg-1和alg-2的表达或活性允许它们调节IIS中不同的基因组， 控制成年动物寿命的途径。在目标1和2中，遗传基础和潜在组织 负责alg-1和alg-2的相反寿命功能的具体活动将是 测定用于检测ALG-1结合的特异性miRNA和靶标的尖端方法 ALG-2将用于目标3。这将导致第一个miRNA特异性靶位点的图谱， 成年动物，并提供了前所未有的见解alg-1和alg-2在IIS中的直接作用， 也许是其他的长寿途径。此外，通过揭示成年人中的miRNA靶向景观， C. elegans将为研究保守的miRNAs的长寿作用建立一个新的基础， 其他物种的目标。这项研究的另一个广泛的影响是，它将揭示两种蛋白质如何 被认为是多余的，在老龄化中扮演着相反的角色，这将为考虑 背景对于任何途径中相关基因功能的重要性。此外，方法 在此用于鉴定miRNA特异性靶位点的方法通常适用于整个系统，因此， 将有助于消除将miRNA与其内源性靶位点匹配的长期障碍。 最后，本工作的一个长期目标是为基因修饰策略的合理设计做出贡献 意图预防或抵消与年龄有关的疾病的表达。