miRNA-449与miRNA-34b/c对精子发生调控机制的研究

我们前期的研究发现，miR-449与miR-34b/c均高表达于小鼠睾丸，提示其在精子发生中发挥重要作用。但在实验室常规环境下，miR-449-/-与miR-34b/c-/-小鼠的表型正常。其在应激条件下表型如何？目前尚无报道。此外，miR-34b/c在miR-449-/-小鼠睾丸中代偿升高，且miR-449和miR-34b/c具有相同种子序列和共同靶基因，提示二者功能类似，从而功能补偿。为明确二者在精子发生中的作用及机制，本项目拟开展三方面研究：研究应激条件下miR-449-/-和miR-34b/c-/-小鼠的表型及机制；构建miR-449与miR-34b/c双基因敲除小鼠并研究其表型及机制；探索miR-449-/-小鼠中miR-34b/c代偿升高的机制。本项目旨在阐明miR-449和miR-34b/c在哺乳动物精子发生过程中的调控机制,并为男性不育症患者提供新的诊断标志物和治疗新思路。

We have recently demonstrated that both miRNA-449 and miRNA-34b/c were abundantly expressed in the mouse testis, suggesting they may play critical roles in spermatogenesis. However, miR-449 knockout mice (miR-449-/-) or miR-34b/c knockout mice (miR-34b/c-/-) have normal phenotypes in both testis and epididymis, and these knockout mice possesse normal fertility under controlled lab conditions. How about their phenotypes under stress conditions? It is not clear up till now. We also found that the expression levels of miR-34b/c were increased in miR-449-/- mice. In addition, miR-449 and miR-34b/c shared the same "seed sequence" and targeted the same set of mRNAs,which may reflect a compensatory effect. In this project, we will first explore the phenotypes and the mechanisms of the miR-449-/- mice and miR-34b/c-/- mice under stress conditions such as heat shock,nerveness,and radiation. Secondly, we plan to generate miR-449 and miR-34b/c double knockout mice (miR-449-/- & miR-34b/c-/-) to unveil the potential phenotypes and mechanisms. Finally, we will uncover the molecular mechanisms of miR-34b/c compensatory role in miR-449-/- mice. This project aims to elucidate the mechanisms by which miRNAs, specifically miR-449 and miR-34b/c, control mammalian spermatogenesis, and it will also offer new diagnostic biomarkers and a potential novel strategy for male infertility treatment.