Hormonal control of Serotli cell maturation and function

该项目将确定雄激素在支持细胞中的关键作用，支持细胞是一种独特的高度分化的细胞，为精子的产生提供必要的营养和结构支持。雄激素通过雄激素受体（AR）起作用，雄激素受体对启动和维持精子发育至关重要。在目前nhmrc资助的研究中，我们成功地建立了新的小鼠模型，旨在研究AR，特别是其在Sertoli细胞中的基因表达调控。我们发现，支持细胞内的基因组AR活性对于“诱导”完整精子发育至关重要。正在进行的工作将开发独特的“可诱导”转基因模型，这将首次允许在“发育”和“成年”睾丸中选择性分析Sertoli AR。我们的创新模型将允许AR功能在任何发展阶段打开或关闭，提供独特的机会来确定关键的AR调节因子和途径，控制精子产生的诱导、维持或恢复。在过去的NHMRC研究中，我们创建了一种新的转基因模型来研究另一种主要的生殖激素FSH。利用“hpg”小鼠的激素缺乏背景，我们发现雄激素和FSH在形成精子的发育中的“减数分裂”生殖细胞中协同作用。使用最新的微阵列基因技术，我们生成了具有或不具有FSH活性的雄激素调节基因数据集，并结合我们独特的转基因AR和FSH模型，将用于识别早期睾丸反应中的关键途径，包括雄激素-FSH协同作用增强的途径。我们的研究将提供睾丸AR作用的精确作用和途径的新知识，最终确定关键的遗传和调节因子作为显著改善男性不育，性腺肿瘤或避孕治疗的靶点。

This project will determine the key roles of androgen in the Sertoli cell, a unique highly specialised cell that provides essential nutritional and structural support for sperm production. Androgen acts via the androgen receptor (AR), which is vital for initiating and maintaining sperm development. In current NHMRC-funded research we successfully established new mouse models designed to study AR, in particular its regulation of gene expression, in the Sertoli cell. We revealed that genomic AR activity within Sertoli cells is essential for 'induction' of complete sperm development. Ongoing work will develop unique 'inducible' transgenic models that will allow, for the first time, selective analysis of Sertoli AR in both 'developing' and 'adult' testes. Our innovative models will allow AR function to be switched on or off at any stage of development, providing unique opportunity to determine the key AR-regulated factors and pathways controlling induction, maintenance or restoration of sperm production. In past NHMRC research we created a novel transgenic model to study another major reproductive hormone, FSH. Using the hormone-deficient background of 'hpg' mice, we found that androgen and FSH act synergistically in the developing 'meiotic' germ cells that form sperm. Using the latest microarray gene technology we generated datasets of androgen-regulated genes with or without FSH activity, which combined with our unique transgenic AR and FSH models, will be used to identify key pathways, including those enhanced by androgen-FSH synergism, in the early testicular response. Our research will provide new knowledge of the precise roles and pathways of testicular AR actions, to ultimately identify key genetic and regulatory factors as targets for significantly improved therapy for male infertility, gonadal tumours, or contraception.