Roles and mechanisms of action of nuclear receptors in steroidogenesis

核受体在类固醇生成中的作用和作用机制

• 批准号: 262224-2010
• 负责人: Tremblay, JacquesJ
• 金额: $ 3.35万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=480189
• 关键词: Roles; mechanisms; action; nuclear; receptors

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.

睾丸间质细胞是雄性动物体内主要的睾酮生成细胞。这些细胞对于男性外生殖器、性附属腺、增加肌肉质量以及产生成熟精子的正常发育是不可或缺的。睾丸间质细胞的功能是由垂体促黄体激素（LH）严格控制。LH与位于Leydig细胞表面的受体结合，从而触发几种细胞内信号传导途径（主要是cAMP/PKA途径）的激活，导致基因表达和类固醇激素产生增加（类固醇生成）。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识别这些因素并确定其作用机制。我认为在这一过程中起重要作用的转录因子家族是核受体家族，特别是COUP 77和COUP-TFII。与我的假设一致，我们已经表明，这些因素是类固醇基因表达的重要调节因子。我们还分析了E77表达本身是如何响应各种刺激而调节的。因此，不同的，但互补的最先进的分子和细胞生物学的方法通常用于阐明LH诱导的性腺类固醇生成，男性生殖功能的关键过程中，这个特定的转录调节因子家族所发挥的作用。