Hormonal Regulation of Sertoli cell function

本项目旨在研究激素对支持细胞发育和功能的控制。在睾丸中，这些高度专业化的细胞为精子产生提供必要的营养和结构支持。在目前由NHMRC支持的研究中，我们创建了一个独特的小鼠模型来研究两种关键生殖激素FSH和睾酮在精子发生中的单独作用。这一新的方法包括在激素缺乏的HPG小鼠的背景下选择性表达转基因FSH，HPG小鼠通常既缺乏雄激素又缺乏FSH。我们的分析表明，FSH为支持细胞和早期生殖细胞的增殖提供了主要刺激，而FSH在精子形成的后期阶段需要睾酮。在这项建议中，我们现在计划研究FSH和支持细胞发育的关键出生后阶段中类固醇的变化。我们将研究FSH和类固醇的联合作用，包括雌二醇在支持细胞和生殖细胞功能中的有争议的作用，这些都可能对精子产生和男性生育能力产生深远的影响。我们还将建立独特的小鼠模型，以解决睾丸中雄激素作用机制的基本问题，以及支持细胞和邻近小管周围细胞中雄激素受体表达对整体睾酮反应的要求。此外，我们将使用新的微阵列基因筛选技术来识别支持细胞增殖过程中FSH和雄激素调节的基因途径。这项研究与环境类固醇影响人类睾丸发育和减少精子数量这一有争议的观点相关，并提供了揭示以前无法解释的男性不育或睾丸癌的新原因的可能性，并有助于开发更好的激素男性避孕策略，以及男性不育症或癌症的治疗。

This project aims to study the hormonal control of Sertoli cell development and function. In the testis, these highly specialised cells provide essential nutritional and structural support for sperm production. In current NHMRC-supported research we created a unique mouse model to study the individual roles of two key reproductive hormones FSH and testosterone in spermatogenesis. This novel approach involved the selective expression of transgenic FSH on the hormone-deficient background of hpg mice, which normally lack both androgens and FSH. Our analysis revealed that FSH provided the main stimulation for Sertoli cell and early germ cell proliferation, whereas FSH required testosterone for later stages of sperm formation. In this proposal we now plan to investigate FSH and the changing steroidal contributions during the critical postnatal stage of Sertoli cell development. We will study individual of combined actions of FSH and steroids, including the controversial role of estradiol in Sertoli and germ cell function, which may all have profound consequences on sperm production and male fertility. We will also establish unique mouse models to address fundamental questions about the mechanisms of androgen actions in the testis, and the requirement for androgen receptor expression in Sertoli and neighbouring peritubular cells for the overall testosterone response. Furthermore, we will use new microarray gene screening technology to identify the FSH- and androgen-regulated gene pathways during Sertoli cell proliferation. This research has relevance to the controversial view of environmental steroids affecting human testicular development and reducing sperm counts, and offers the potential to uncover new causes of previously unexplained male infertility or testicular cancers, and to help develop better strategies for hormonal male contraceptives, and treatments for male infertitliy or cancer.