CFTR和CatSper1相互作用及其信号途径参与精子受精过程的机制研究

In sperm, CFTR mediates HCO3- entry, which in turn increases cAMP/PKA production and protein tyrosine phosphorylation that are associated with sperm capacitation, hyperactivation and acrosome reaction. Then, is CFTR invovled in the Ca2+ mobilization mediated by sperm tail calcium channel CatSper1? Interestingly, we have previously observed that, CatSper1 inhibitors could antagonize sperm progressive motility and protein tyrosine phosphorylation from asthenospermia induced by CFTR agonist. Furthermore, CFTR inhibitor (CFTRinh-172) and sAC inhibitor (sACinh-KH7) could decrease sperm progressive motility and Ca2+ mobilization activated by progesterone (P4), respectively. These results indicate a potential functional interaction between CFTR and CatSper1. This prompted us to hypothesize that CFTR may interact with CatSper1, which then activates cAMP and Ca2+-dependent signaling pathway that are involved in sperm progressive motility and acrosome reaction. We undertake the present study to test this hypothesis using Confocal, CASA and real-time Ca2+ detection. The aim of this study is to explore the functional interaction of CFTR and CatSper1, the invovlement of CFTR in P4 on sperm chemotaxis and the non-genomic effects of P4 and related signaling pathway, so as to establish the key role of CFTR and CatSper1 in human sperm fertilization and their pathophysiological relevance in male infertility.

CFTR通透HCO3-激活sAC/cAMP/PKA途径，参与精子超活化和顶体反应。那么，它是否参与钙通道CatSper1对钙离子的动员？我们前期实验显示：CFTR激动剂促进低活力精子前向运动和酪氨酸磷酸化，CatSper1抑制剂可拮抗此过程；孕酮（P4）激活CatSper1，促进人精子前向运动和钙离子动员，此过程可被CFTR抑制剂和sAC抑制剂所拮抗。因此，推测CFTR和CatSper1相互作用并参与精子前向运动和顶体反应。本项目拟：1）研究CFTR与CatSper1共同启动cAMP和钙离子依赖的信号通路；2）证明赤道板CFTR参与P4对精子的趋化；3）探讨P4激活CFTR和CatSper1参与精子受精的机制。本项目对阐明CFTR和CatSper1在精子受精中的作用具有重要意义，也将为弱精子症的发病机理提供理论依据。