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

 描述(申请人提供)：microRNAs(MiRNAs)代表一类新的普遍存在的高度丰富的基因调控元件，在植物和动物的基因表达调控中发挥重要作用。像转录因子一样，miRNAs有可能调节数以千计的基因，事实上，预测表明很大一部分人类基因组是miRNAs的靶标。与此一致的是，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的功能仍未确定。我们以前已经发现了在衰老过程中差异表达的多个miRNAs，并发现其中几个在长寿、热量限制和应激抵抗中发挥了重要作用。当前建议的总体目标是描绘将应激反应与miRNAs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，这项建议旨在利用模式生物秀丽线虫：1)结合转录组调查和功能遗传学，确定与衰老相关的miRNAs调控的miRNA靶基因和途径；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miRNAs的上游遗传调节因子 作为衰老相关miRNAs上游的候选调控因子；以及3)决定了miRNAs在神经退行性变和蛋白毒性应激模型中的功能。模式生物秀丽线虫非常适合本科生的研究环境，它是本项目中描述的研究目标的选择模型。鉴于miRNAs及其靶标在不同地层中的高度保守性，我们预计在线虫中关于miRNA在抗逆性中作用的遗传网络的发现将适用于人类具有生物医学意义的疾病。

 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.