TGF-β1信号通路调节睾丸间质细胞分泌雌激素的机制

正常水平的雌激素在男性生殖系统中同样发挥着重要的作用，雌激素在睾丸局部主要由间质细胞（LCs）合成，但其分泌的具体调控机制并不完全清楚。我们的前期工作表明，成年大鼠LCs中TGF-β1通过下调CYP19的表达，抑制P450芳香化酶的活性和雌激素的分泌，而且TGF-β1还能降低CYP19转录因子SF-1的表达，提示TGF-β1信号通路对CYP19的转录调控是影响LCs中雌激素分泌的重要机制。本项目拟先在培养的LCs中，初步阐明TGF-β1、Smads、SF-1以及其它共调控因子对CYP19的转录抑制机制；进而构建LCs特异性Smad4敲除小鼠，观察阻断TGF-β1信号通路对LCs合成雌激素和睾丸表型的影响，并深入探讨LCs中TGF-β1通路调控雌激素合成的信号网络；最后通过对临床间质细胞瘤患者标本的分析，验证细胞和动物实验的发现。本项目的实施有助于全面揭示男性睾丸中雌激素合成紊乱的分子机制。

Normal levels of estrogen also play an important role in male reproductive system. Leyding cells (LCs) in the adult testis have been identified as the major sites of synthesis of this sex hormone. However, the regulative mechanism of estrogen secretion from LCs is not entirely clear yet. Our previous work indicated that TGF-β1 had a significant inhibitory effect on P450arom activity and estrogen secretion via down-regulating the expression of CYP19 in mature rat LCs. Moreover, TGF-β1 also decreased the expression of SF-1, one of the transcription factors of CYP19. Therefore, transcriptonal regulation of CYP19 by TGF-β1 signal pathway is an important mechanism controlling estrogen secretion in LCs. This project intends to initially clarify the mechanism by which TGF-β1，Smads，SF-1 and other co-regulators exert their inhibitory effect on CYP19 transcription in the cultured LCs. Then, we aim to further observe the effect of TGF-β1 signal pathway on LCs estrogen synthesis, as well as testis phenotypes by using Leydig cell-specific Smad4 knockout mouse model. In this way, we can probe into the signal network of TGF-β1 regulation of estrogen synthesis. Finally，the findings in the cellular and knockout mice studies will be validated by analyzing clininical LC tumor samples. This project would contribute to reveal the molecular mechanism of disorders of male testicular estrogen synthesis thoroughly.