mir-83在衰老及衰老相关疾病中的作用及机理研究

衰老不仅是机体功能逐渐降低的过程，还和神经退行性疾病等重大疾病密切相关。在线虫等模式生物中的研究发现衰老是一个受着多条保守信号通路调节的可控过程，其中一条重要的通路是由“限制饮食”而激活的。微小RNA是一类22个核苷酸左右的非编码小RNA，在多种生命活动中发挥着重要作用。但是，目前微小RNA在“限制饮食”信号通路以及衰老中的作用还知之甚少。申请人在前期研究中通过大规模测序获得了线虫中受“限制饮食”通路调控的微小RNA转录组，经系统筛选后发现mir-83被该通路抑制并对衰老有重要的调控作用，并初步发现mir-83可能与多个蛋白质降解相关的基因存在相互作用。而且，mir-83的缺失突变在多个神经退行性疾病模型中能够显著减轻症状。我们拟利用线虫与哺乳动物细胞深入研究mir-83在衰老及其相关疾病中的功能和作用机理，在解析其作用的分子网络的基础上进一步阐明“限制饮食"通路延缓衰老的分子机制。

Ageing is not only a progressive decline of body functions, but also tightly associated with a series of ageing-related diseases including neurodegenerative diseases. From the genetic studies in C. elegans and other model organisms, ageing is discovered to be carefully regulated by multiple conserved signaling pathways. One of the longevity pathways is the signaling from dietary restriction (DR). MicroRNAs are a class of non-coding RNAs with ~22 nt, playing important roles in multiple biological processes. However, the function of microRNAs in DR pathway and ageing is barely known. In our preliminary work, we obtained a transcriptome of DR-regulated microRNAs through deep sequencing. Subsequent screening identified a conserved microRNA, mir-83, which is down-regulated under DR, regulating ageing. Its knock-out mutant significantly relieved symptoms induced by several neurodegenerative disease models. Preliminary bioinformatics analysis also showed that mir-83 could interact with multiple genes involved in protein degradation. This project will explore the functions and mechanisms of mir-83 in ageing, and ageing-related diseases, using C. elegans and mammalian cell cultures as models. In addition to analyzing the molecular network underlying this microRNA’s function, this project also aims to further elucidate the molecular mechanisms of DR-induced longevity.