The role of microRNAs in aging.

描述（由申请人提供）： microRNAs（miRNAs）是一类新型的基因调控元件，在动植物基因表达和发育过程中发挥重要作用。miRNA是内源性的小的非编码RNA，其通过与靶基因的碱基配对来抑制基因表达，并通过仍在阐明的机制来沉默它们的表达。尽管miRNAs在高等生物中高度丰富并被预测靶向大部分基因，但到目前为止，miRNAs仅涉及少数生物学作用。绝大多数miRNAs的功能仍然是个谜。miRNA家族的两个创始成员lin-4和let-7首先在C. elegans，它调节线虫幼虫发育的时间。最近，这两种miRNAs都与其他生物学领域有关，如癌症和寿命。最近的研究表明，lin-4及其靶lin-14的突变显著影响C.优雅此外，还利用基因芯片技术对C. elegans揭示了衰老过程中miRNA表达的动态变化。这些观察结果表明，miRNAs可能在影响寿命的途径中发挥作用。该提案旨在研究已知miRNA在衰老中的作用，在老年动物中鉴定新的miRNA，以及其功能的遗传机制。为了实现这些目标，miRNAs将首先从衰老的C.线虫和表现出寿命改变的突变蠕虫。对老年动物富集群体的关注将允许表征新miRNA在寿命中的潜在作用。然后将新鉴定的miRNA以及先前表征的异时基因突变并测定蠕虫的寿命效应。我们预测尚未鉴定的miRNAs可能调节寿命或作为衰老疾病的生物标志物。最后，为了了解其在衰老中作用的遗传机制，将通过多种技术研究这些miRNA突变的下游效应，包括GFP：融合表达分析和已知寿命途径中基因的上位性关系。相关性：了解衰老的生物学机制是当前医学研究的一个关键目标。C.线虫寿命短。使其成为研究衰老的首选生物。MicroRNA是一类新的调控元件，它首先在C.已经被证明可以调节寿命。我们试图鉴定在衰老中起作用的新的miRNAs，并研究它们的功能。鉴于microRNA在物种间的高度保守性，这项研究的发现可能会导致衰老疾病的新生物标志物，并将为我们对高等生物和人类衰老的理解提供信息。

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) constitute a novel class of gene regulatory elements with important roles in the control of gene expression and development in plants and animals. miRNAs are endogenous, small non-coding RNAs which inhibit gene expression by base pairing with target genes and silencing their expression via mechanisms which are still being elucidated. Although highly abundant and predicted to target a wide proportion of genes in higher organisms, miRNAs have so far only been implicated in handful of biological roles. The function of the vast majority of miRNAs remains a mystery. Two founding members of the miRNA family, lin-4 and let-7, were first identified in the heterochronic pathway of C. elegans, which regulates the timing of larval development in the nematode. Both miRNAs have more recently been implicated in other biological areas, such as cancer and life span. Recent work has demonstrated that mutations to lin-4 and its target lin-14 significantly affect the lifespan of C. elegans. In addition, microarray analysis in C. elegans has revealed dynamic miRNA expression changes during aging. These observations suggest that miRNAs may function in pathways that impact life span. This proposal seeks to study the role of known miRNAs in aging, the identification of novel miRNAs in aged animals, and the genetic mechanisms underlying their function. In order to achieve these objectives, miRNAs will first be cloned from aged populations of C. elegans and from mutant worms that exhibit altered lifespan. The focus on enriched population of aged animals will allow the characterization of potential roles for new miRNAs in lifespan. Newly identified miRNAs as well as previously characterized heterochronic genes will then be mutated and assayed for lifespan effects in adult worms. We predict that yet unidentified miRNAs may modulate life span or serve as biomarkers of diseases of aging. Finally, in order to understand the genetic mechanisms underlying their role in aging, the downstream effects of mutations to these miRNAs will be studied by a variety of techniques including GFP:fusion expression analysis and epistastic relationship to genes in known life span pathways. Relevance: Understanding the biological mechanisms underlying aging is a key goal of current medical research. The short life span of the nematode C. elegans makes it the organism of choice in the study of aging. MicroRNAs, a novel class of regulatory elements first identified in C. elegans, have now been shown to modulate life span. We seek to identify new miRNAs with a role in aging and to study their function. Given the high conservation of microRNAs across species, findings from this research may lead to new biomarkers of diseases of aging and will inform on our understanding of aging in higher organisms and humans.