转录因子LISCH7参与调控睾丸支持细胞乳酸盐代谢的机制研究

由于支持细胞（SCs）功能异常改变导致乳酸盐分泌障碍，引起精母细胞和精子细胞大量凋亡是诱发少精症、无精症的重要原因。我们前期工作发现，特异性表达于SCs的转录因子LISCH7在人唯支持细胞综合征睾丸组织中异常低表达；细胞学实验和SCsLISCH7-/-小鼠模型均显示敲除LISCH7显著抑制SCs乳酸盐合成；生精细胞分泌TNF-α、SCs中的乳酸脱氢酶A（LDHA）可能分别是与LISCH7作用的上、下游信号。据此推测生精细胞分泌TNF-α与SCs中的LISCH7/LDHA信号通路一起构成调控SCs乳酸盐代谢的重要旁分泌信号网络，本课题以SCsLISCH7-/-小鼠为平台，拟深入研究SCs乳酸盐合成过程中TNF-α/LISCH7/LDHA的相互作用关系，阐明LISCH7通过调控LDHA转录表达干预SCs乳酸盐合成的分子机制，为深入理解能量代谢紊乱致精子发生障碍的复杂发病机理提供重要新线索。

Dysfunction of lactate production in testicular Sertoli cells (SCs) induces massive apoptosis in spermatocytes and spermatids, thus contributing essentially to the pathogenesis of oligozoospermia and azoospermia. In our previous work, we observed that SCs-specific expression of the liver-specific bHLH-Zip transcription factor (LISCH7) was significantly downregulated in testicular tissues from patients with Sertoli cell only syndrome (SCOS). Subsequent assays using SCs and SCsLISCH7-/- mouse model both revealed that ablation of the endogenous LISCH7 significantly impairs lactate metabolism in SCs. Moreover, TNF-α that is secreted by germ cells and lactate dehydrogenase A (LDHA) in SCs may function as the direct upstream and downstream signaling pathways of LISCH7. On this basis, we hypothesize that TNF-α and LDHA, in concert with LISCH7, may form into an important paracrine signaling network regulating fundamentally the lactate metabolism in SCs. In the current study, by using SCsLISCH7-/- mouse model, we aim to further investigate the functional details of the TNF-α/LISCH7/LDHA cascade along the production of lactate in SCs, and to elucidate the molecular mechanism underlying the regulation of lactate metabolism by LISCH7 via transcriptional regulation of LDHA. Overall, our systematic analysis should pave the way for a better understanding of the complicated pathogenesis of spermatogenic failure caused by energy metabolism disturbance.