HORMONAL REGULATION OF MAMMALIAN SPERMATOGENESIS

成年哺乳动物的精子发生高度依赖于睾酮。 雄激素受体定位于支持细胞，使其有可能 睾丸激素的作用是通过支持细胞来实现的。然而， 令人惊讶的是，人们对睾丸激素在体内的作用知之甚少。 睾丸内睾酮水平降低会导致生殖细胞数量增加 细胞凋亡，提示睾酮可能是细胞存活的一个因素。 睾酮保护生殖细胞免于凋亡的机制(S) 死亡几乎没有受到关注。Fas系统，包括 支持细胞Fas配体，生殖细胞和生殖细胞表达的Fas Fas参与了睾丸生殖细胞的凋亡。Bc l-2 蛋白质家族在细胞凋亡的调控中起着核心作用 多种细胞类型的细胞死亡。这些蛋白质中的一些， 包括Bcl2和Bclxlong，抑制细胞死亡，而其他，包括 Bax和BclxShort，促进细胞凋亡。到目前为止，我们还不知道是哪一个 这些蛋白质存在于特定的生殖细胞中，也不知道它们是如何反应的 与睾丸激素有关。这项资助的一个中心假设是睾丸激素 通过对支持细胞的影响促进生殖细胞的存活 细胞/生殖细胞Fas系统及其参与的Bcl2家族蛋白 细胞存活/细胞死亡。我们将首先确定在何种程度上 ABP结合睾酮解释了睾丸内的高密度 睾丸激素浓度是维持精子发生所必需的。 成年大鼠。然后我们将测试睾丸激素的概念，通过 Sertoli细胞影响Fas系统，并通过这个系统影响细胞 Bcl2家族的存活/细胞死亡蛋白，从而影响 核小体间裂解和随后的细胞凋亡性死亡 生殖细胞就会出现。这些研究的结果与 Jarow博士在项目I中提出的研究结果应该得到澄清 调节大鼠和人精子发生的共同原则， 并在最后提供了具体的机制信息(S) 哪种睾丸素在体内作用于调节精子发生。

Adult mammalian spermatogenesis is highly dependent upon testosterone. Androgen receptors are localized to Sertoli cells, making it likely that the effects of testosterone are mediated via the Sertoli cell. However, remarkably little is known about how testosterone functions in vivo. Reduced intratesticular testosterone can lead to increased germ cell apoptosis, suggesting that testosterone may serve a cell survival factor. The mechanism(s) by which testosterone protects germ cells from apoptotic death has received very little attention. The Fas system, including Sertoli cell Fas ligand, and Fas, expressed by germ cells, and germ cell Fas, has been implicated in testicular germ cell apoptosis. The Bcl-2 family of proteins plays a central role in the regulation of apoptotic cell death in a variety of cell types. Some among these proteins, including Bcl-2 and Bcl-xlong, inhibit cell death, while others, including Bax and Bcl-xshort, promoter apoptosis. As yet, we do not know which of these proteins is present in particular germ cells, nor how they respond to testosterone. A central hypothesis of this grant is that testosterone promotes the survival of germ cells via its effects on the Sertoli cell/germ cell Fas system, and on the Bcl-2 family of proteins involved in cell survival/cell death. We will first determine the extent to which binding of testosterone by ABP explains the high intratesticular testosterone concentration is required to maintain spermatogenesis in the adult rat. We then will test the concept that testosterone, acting through the Sertoli cell, influences the Fas system and, through this system, cell survival/cell death proteins of the Bcl-2 family, thereby influencing whether or not internucleosomal cleavage and subsequent apoptotic death of germ cells occurs. The results of these studies, taken together with the results of studies proposed by Dr. Jarow in Project I, should elucidate common principles involved in regulating spermatogenesis in rats and men, and at long last should provide concrete information on mechanism(s) by which testosterone acts in vivo to regulate spermatogenesis.