Androgne Recptor Gene Transcription in Sertoli Cells

项目2摘要 主要研究者：Terry R.布朗 大量研究表明，雄激素受体（AR）及其配体睾酮（T）， 是正常精子生成所必需的最近发表的观察表明， AR基因的细胞特异性条件性敲除不产生精子提供了AR 支持细胞中的表达是雄性生育力绝对需要的。然而，尽管重要的是 AR在精子发生中的调节作用，目前还没有全面的努力来了解AR是如何 表达本身是有规律的。本申请的重点是定义分子和机制 驱动支持细胞中AR基因的表达。 大鼠、小鼠和男性的支持细胞表现出高度一致的AR表达模式。期间 青春期成熟，当精子发生成为一个越来越有效的过程，有一个 Sertoli细胞中AR表达增加。在成年期，支持细胞中的AR表达模式是 与相邻生精细胞在周期各阶段的进展同步 生精上皮细胞重要的是，AR表达水平最高的阶段 基因是最敏感的雄激素刺激的损失。因此，这个问题的核心假设 建议是，支持细胞在青春期成熟和成人中表达AR， 由转录因子及其同源顺式作用调节因子的一小部分的活性决定， AR基因中的元素。这些分子中重要的是那些调节成熟的 和AR基因转录的阶段特异性变化。这项建议的三个具体目标将检验 这一假设通过鉴定转录因子和同源顺式作用调控元件， 大鼠AR基因启动子，所述启动子是通过以下方式表达AR的成熟依赖性和阶段特异性所需的 Sertoli细胞，并确定这些元件和因子是否是AR体内表达所需的， 支持细胞。 人口控制，以及繁殖的成功和失败，仍然是公众的重大问题， 健康因此，我们提出的实验应该揭示调节AR的重要机制， 表达不仅在啮齿动物，而且在人类，从而有助于我们了解男性 生育

ABSTRACT-PROJECT 2 Principal Investigator: Terry R. Brown Numerous studies have demonstrated that the androgen receptor (AR) and its ligand, testosterone (T), are required for normal spermatogenesis. Recently published observations showing that mice with Sertoli cell specific conditional knockout of the AR gene do not produce sperm provide definitive proof that AR expression in Sertoli cells is absolutely required for male fertility. However, despite the importance of the AR in the regulation of spermatogenesis, there has been no comprehensive effort to understand how AR expression itself is regulated. The focus of this application is to define the molecules and mechanisms that drive expression of the AR gene in Sertoli cells. Sertoli cells in rats, mice and men exhibit highly concordant patterns of AR expression. During pubertal maturation, when spermatogenesis becomes an increasingly efficient process, there is an increase in AR expression in Sertoli cells. In adulthood, the pattern of AR expression in Sertoli cells is synchronized with the progression of the neighboring spermatogenic cells through the stages of the cycle of the seminiferous epithelium. Importantly, the stages with the highest level of expression of the AR gene are the most sensitive to the loss of androgen stimulation. Thus, the central hypothesis of this proposal is that the expression of AR by Sertoli cells, both during pubertal maturation and in the adult, is determined by the activity of a small subset of transcription factors and their cognate cis-acting regulatory elements within the AR gene. Important among these molecules are those that regulate the maturational and stage-specific changes in AR gene transcription. The .three specific aims of this proposal will test this hypothesis by identifying the transcription factors and cognate cis-acting regulatory elements in the rat AR gene promoter that are required for maturation-dependent and stage-specific expression of AR by Sertoli cells and determine if those elements and factors are required for the in vivo expression of AR by Sertoli cells. Population control, as well as reproductive success and failure, remain significant issues for public health. Thus, our proposed experiments should reveal important mechanisms that regulate AR expression not only in rodents but also in humans, and thereby contribute to our understanding of male fertility.