DDR2在睾丸中表达的功能及调控机制研究

发布时间：2018-04-05 20:45

本文选题：盘状结构域受体2　切入点：精子发生　出处：《第四军医大学》2016年博士论文

【摘要】：研究背景:盘状结构域受体2(Disoind domain receptor 2,DDR2)持续表达于正常人类及小鼠睾丸间质细胞中,且DDR2slie/slie小鼠呈现生精障碍表型,但其发病机制及DDR2在睾丸精子发生中的作用及调节机制并不清楚。研究目的:揭示DDR2sile/slie小鼠生精障碍的机制,明确DDR2表达在精子发生中的功能及调节机制。实验方法:通过构建多种生精障碍的小鼠动物模型,结合临床不育病人睾丸标本病理切片,检测DDR2在不同生精障碍中的表达,探索其在精子发生中的功能。研究结果:在本研究中我们发现:睾丸间质细胞DDR2表达可以消耗I型胶原并调节睾丸间质胞外基质中I型胶原含量从而调节间质细胞睾酮合成;DDR2缺失会导致I型胶原异常累积抑制睾酮合成并导致精子发生障碍。唯支持细胞综合征患者生精小管内支持细胞雄激素受体表达水平下降会引起睾丸支持细胞异常表达DDR2,异常表达的DDR2会促进支持细胞胞吞作用并代偿性修复受损的血睾屏障。另外,非梗阻性无精症及隐睾患者睾丸凋亡的生精细胞胞核表达DDR2;异常表达的DDR2是由生精障碍睾丸中异常升高的肿瘤坏死因子α(TNF-α)活化核因子κB(NF-κB)进而转录调控DDR2诱导引起的;这种异常升高的DDR2可以通过抑制FasL的表达进而抑制生精细胞凋亡。结论:我们的研究证实DDR2通过与多种因子相互作用及调节多个信号通路,在维持雄性睾丸的正常精子发生及修复不育睾丸的生精障碍中发挥着重要作用。
[Abstract]:Background: 2(Disoind domain receptor 2 DDR2) is expressed in normal human and mouse testicular stromal cells, and DDR2slie/slie mice present spermatogenic disorder phenotype.However, its pathogenesis and the role and regulation of DDR2 in testicular spermatogenesis are unclear.Objective: to explore the mechanism of spermatogenesis in DDR2sile/slie mice and to clarify the function and regulation of DDR2 expression in spermatogenesis.Methods: the expression of DDR2 in different spermatogenic disorders and its function in spermatogenesis were detected by constructing animal models of various spermatogenic disorders and combining with pathological sections of testis of infertile patients.Results: in this study, we found that the expression of DDR2 in Leydig cells of testis can consume type I collagen and regulate the content of type I collagen in the extracellular matrix of testis, and thus regulate the testosterone synthesis of stromal cells.Abnormal accumulation of collagen inhibits testosterone synthesis and leads to spermatogenesis disorders.The decreased expression of androgen receptor in Sertoli cells in seminiferous tubule of patients with Sertoli syndrome may induce abnormal expression of DDR2 in Sertoli cells. Abnormal expression of DDR2 can promote the cytotoxicity of Sertoli cells and compensatory repair of the damaged blood testis barrier.In addition, the apoptotic spermatogenic nucleus of testis in patients with non-obstructive azoospermia and cryptorchidism expressed DDR2.The abnormal expression of DDR2 was induced by the activation of nuclear factor- 魏 B, NF- 魏 B), and the transcription regulation of DDR2, by the abnormal elevation of tumor necrosis factor 伪 -TNF- 伪 in spermatogenic disorder testis.This abnormally elevated DDR2 inhibits spermatogenic cell apoptosis by inhibiting the expression of FasL.Conclusion: our results suggest that DDR2 plays an important role in maintaining normal spermatogenesis in male testis and repairing spermatogenic disorders of sterile testis by interacting with multiple factors and regulating multiple signaling pathways.
【学位授予单位】：第四军医大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R698.2

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