HORMONAL REGULATION OF MAMMALIAN SPERMATOGENESIS

成年哺乳动物精子发生高度依赖于睾酮。 雄激素受体定位于支持细胞，这使得 睾酮的作用是通过支持细胞介导的。然而，在这方面， 对于睾丸激素在体内的作用知之甚少。 睾丸内睾酮减少可导致生殖细胞增加 凋亡，表明睾酮可能是细胞存活因子。 睾酮保护生殖细胞免于凋亡的机制 死亡很少受到关注。FAS系统，包括 支持细胞Fas配体和由生殖细胞表达的Fas，以及生殖细胞 Fas与睾丸生殖细胞凋亡有关。该Bcl-2 蛋白质家族在细胞凋亡的调节中起着核心作用。 多种细胞类型中的细胞死亡。在这些蛋白质中， 包括Bcl-2和Bcl-xlong，抑制细胞死亡，而其他的，包括 Bax和Bcl-xshort，启动子凋亡。到目前为止，我们还不知道 这些蛋白质存在于特定的生殖细胞中， 睾丸激素这项研究的一个核心假设是， 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，并对Bcl-2家族的蛋白质参与 细胞存活/细胞死亡。我们将首先确定 ABP与睾酮的结合解释了睾丸内高的 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，通过 支持细胞影响Fas系统，并通过该系统影响细胞 Bcl-2家族的存活/细胞死亡蛋白，从而影响 核小体间分裂和随后的凋亡性死亡 生殖细胞发生。这些研究的结果，连同 Jarow博士在项目I中提出的研究结果，应阐明 涉及调节大鼠和男性精子发生的共同原则， 最后应提供关于机制的具体资料， 睾丸激素在体内调节精子发生。

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.