Roles and mechanisms of action of nuclear receptors in steroidogenesis

睾丸间质细胞是男性体内产生睾酮的主要细胞。这些细胞对于男性外生殖器、性附腺的正常发育、肌肉质量的增加以及成熟精子的产生都是不可或缺的。间质细胞的功能受到脑下垂体促黄体激素(LH)的严格控制。黄体生成素与间质细胞表面的黄体生成素受体结合，从而激活多种细胞内信号通路(主要是cAMP/PKA通路)，导致基因表达增加和类固醇激素的产生(类固醇合成)。这些信号通路下游的转录因子及其作用机制仍然知之甚少。因此，本研究计划的目标是确定这些因素并确定它们的作用机制。我认为在这一过程中发挥重要作用的一个转录因子家族是核受体家族，特别是NUR77和COUP-TFII。与我的假设一致，我们已经证明这些因子是类固醇合成基因表达的重要调节因子。我们还在分析NUR77表达本身是如何对各种刺激做出反应的。因此，不同但互补的最先进的分子和细胞生物学方法通常被用来阐明这一特定的转录调节家族在促黄体生成素诱导的性腺类固醇生成中所扮演的角色，这是一个对男性生殖功能至关重要的过程。

Testicular Leydig cells are the main testosterone-producing cells in the male. These cells are indispensable for the proper development of external male genitalia, sex accessory glands, increased muscle mass, as well as production of mature sperm. Leydig cell function is tightly controlled by the pituitary luteinizing hormone (LH). LH binds to its receptor located on the surface of Leydig cells thus triggering activation of the several intracellular signaling pathways (the main one being the cAMP/PKA pathway) leading to increased gene expression and steroid hormone production (steroidogenesis). The transcription factors downstream of these signaling pathways and their mechanisms of action remain poorly understood. Therefore, the goal of the present research program is to identify these factors and to determine their mechanism of action. One family of transcription factors that I believe play an important role in this process is nuclear receptor family, particularly NUR77 and COUP-TFII. Consistent with my hypothesis, we have shown that these factors are important regulators of steroidogenic gene expression. We are also analyzing how NUR77 expression itself is regulated in response to the various stimuli. Thus, different but complementary state-of-the-art molecular and cellular biology approaches are routinely used to elucidate the roles played by this particular family of transcriptional regulators in LH-induced gonadal steroidogenesis, a process critical for male reproductive function.