敲除或抑制Bin2提高雌鼠生殖力、卵泡储备和卵子质量的机制及转化医学研究

如何安全保护和提高女性生殖力是医学研究的热点。目前在小鼠模型上已发表的方案均有靶向性弱或副作用大的缺点。我们发现Bin2在小鼠卵巢中优势表达，全敲后雌鼠生殖力显著增加。Bin2全敲特异性下调p-rps6达一倍而不改变mTOR通路其它分子，并上调自由基清除酶NNT达6倍。提示Bin2全敲不影响正常生理且可实现增加卵泡储备和提高卵子质量的双重效应。进一步，我们鉴定并验证了Bin2上的两个磷酸化位点T423&S424是Bin2直接激活rps6的关键位点。由此我们进行了初步的转化医学研究，发现合成的T423&S424附近多肽可以有效抑制内源Bin2的磷酸化而提高退役鼠生殖力，也可显著恢复化疗药导致的卵巢早衰小鼠的生殖力。本申请计划在基础方面进一步从上、中、下游深入研究Bin2的作用机制，在转化方面系统研究抑制Bin2而延长和保护雌性生殖力的安全性。本项目将为保护和提高女性生殖力提供新的理论依据。

How to protect and increase female fertility safely is a hot topic in medical research. At present, all the published strategies in mouse models have the disadvantages of weak targeting or high side effects. We found Bin2 protein was dominant in mouse ovaries, and global knockout of Bin2 gene significantly increased the fertility of female mice. And Bin2 knockout specifically down-regulated p-rps6 by one fold without altering other molecules in the mTOR pathway, while increased NNT, the free radical-scavenging enzyme, by six fold. These suggested that Bin2 can achieve the dual effects of increasing follicular reserve and improving egg quality without affecting the normal physiology. Further, we identified and verified two phosphorylation sites on Bin2, T423&S424, as key sites for the direct activation of rps6 by Bin2. Therefore, we conducted preliminary translational studies and found that the synthetic polypeptide around T423&S424 can effectively inhibit the phosphorylation of endogenous Bin2 and improve the fertility of retiring mice, and can also significantly restore the fertility of mice with premature ovarian failure induced by chemotherapy. This application plan to further investigate the mechanism of Bin2 function from the upstream, middle and downstream in the aspect of basic research, and systematically study the safety of prolonging and protecting female fertility in the aspect of translational research. This project will provide a new theoretical basis for protecting and increasing human female fertility.