Molecular Mechanisms of miRNA Function in Stress Response and in Models of Diseases of Aging in C. elegans

 描述（由申请人提供）：微小RNA（miRNAs）代表一类新的普遍存在且高度丰富的基因调控元件，在植物和动物的基因表达控制中具有重要作用。像转录因子一样，miRNA有可能调节成千上万的基因，而且，事实上，预测表明，人类基因组的很大一部分是miRNA的靶向。与此相一致的是，miRNAs参与了一系列令人印象深刻的功能，包括发育、癌症和免疫。然而，绝大多数miRNAs的功能仍然是未知的。我们以前已经鉴定了多种在衰老过程中差异表达的miRNA，并发现其中几种在长寿，热量限制和抗应激中的重要作用。目前建议的总体目标是描绘将应激反应与miRNA联系起来的遗传网络，并将这些与生物医学相关的遗传途径联系起来。为此，本提案旨在利用模式生物C。elegans：1）利用转录组学和功能遗传学相结合的方法，确定衰老相关miRNA的靶基因和调控途径; 2）通过表达研究和功能遗传学，通过测试特定转录因子的作用，确定应激相关miRNA的上游遗传调控因子 作为衰老相关miRNA的候选上游调节因子;和3）确定miRNA在神经变性和蛋白毒性应激模型中的功能。模式生物C. elegans非常适合本科生的研究环境，它是本项目所描述的研究目标的选择模型。鉴于miRNAs及其靶基因在地层中的高度保守性，我们预计C. elegans关于miRNA抗应激功能的遗传网络的研究将适用于人类重要的生物医学疾病。

 DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) represent a novel class of ubiquitous and highly abundant gene regulatory elements with important roles in the control of gene expression in plants and animals. Like transcription factors, miRNAs have the potential to regulate thousands of genes, and, indeed, predictions suggest that a significant percentage of the human genome is targeted by miRNAs. Consistent with this, miRNAs have been implicated in an impressive array of functions, including development, cancer, and immunity. Yet, the function of the vast majority of miRNAs remains uncharacterized. We have previously identified multiple miRNAs that are differentially expressed during aging and discovered important roles for several of these in longevity, caloric restriction and stress resistance. The overall goal of te current proposal is to delineate the genetic networks that link stress response to miRNAs and associate these with biomedically relevant genetic pathways. To that end, this proposal aims to utilize the model organism C. elegans to: 1) Identify the miRNA target genes and pathways regulated by aging-associated miRNAs using a combination of transcriptome surveying and functional genetics; 2) Identify upstream genetic regulators of stress-associated miRNAs by testing, via expression studies and functional genetics, the role of specific transcription factors as candidate upstream regulators of aging-associated miRNAs; and 3) Determine the functions of miRNAs in models of neurodegeneration and proteotoxic stress. The model organism C. elegans is ideally suited for an undergraduate research setting and it is the model of choice for the research aims delineated in this project. Given the high conservation of miRNAs and their targets across strata we expect that discoveries made in C. elegans about the genetic networks that underlie miRNA function in stress resistance will be applicable to diseases of biomedical importance in humans.