Hormonal and Paracrine Regulation of Spermatogenesis

描述(申请人提供)：本申请的重点是人类和啮齿动物精子发生的激素和旁分泌调节。项目I(Barry Zirkin和Jonathan Jarow)解决了为什么只有一些接受激素避孕的男性会变成无精子症的生物学机制。对以睾酮(T)为基础的避孕措施的反应中自然产生的种族差异将进行研究，以解决这个生物学问题。我们将比较亚洲和高加索男性在接受基于激素的避孕剂量T前后睾丸内生物活性雄激素的浓度，并将确定hCG[人绒毛膜促性腺激素]诱导的睾丸内生物活性雄激素与精子发生之间的定量关系。这些研究将为开发有效的基于激素的男性避孕药提供重要的新信息，并为T调节男性精子发生的生理机制提供实质性的新见解。雄激素对精子发生的生物学效应是通过支持细胞中的雄激素受体(AR)介导的。项目II(Terry Brown)的主要目标是阐明驱动AR基因在Sertoli细胞中表达的分子机制，并确定控制AR基因青春期成熟依赖和成年期特异性转录的特定转录因子及其顺式作用调控元件。项目III(William Wright)通过研究Sertoli细胞生长因子GDNF、FGF-2和IGF-1的体内功能来关注精子发生的旁分泌调节，这些因子被认为参与了干细胞精原复制和分化的控制。它的中心假设是，分化的生殖细胞通过反馈效应调节支持细胞生长因子的表达，而生长因子反过来又调节干细胞精原细胞的分化和复制。最后，我们提出了一个试点项目(Paul Miller)，该项目基于我们的理解，即生殖细胞DNA容易受到损害，可能是男性不育的一个重要因素。将使用信标适配子开发一种快速、简单的分析方法来评估生殖细胞中DNA氧化损伤的水平，信标适配子是一种能够以高度特异的方式结合配体的寡核苷酸。这些生物传感器将被设计用来测量不育男性精子DNA中的氧化核苷，8-氧脱氧腺苷和8-氧脱氧鸟苷。

DESCRIPTION (provided by applicant): The focus of this application is on the hormonal and paracrine regulation of spermatogenesis in humans and rodents. Project I (Barry Zirkin and Jonathan Jarow) addresses the biological mechanisms that explain why only some men who receive hormonal contraception become azoospermic. Naturally occurring ethnic differences in the response to testosterone (T)-based contraception will be studied to address this biological issue. We will compare intratesticular concentrations of bioactive androgen in Asian and Caucasian men before and after they receive hormone-based contraceptive doses of T, and will determine the quantitative relationship between hCG [human chorionic gonadotropin]-induced intratesticular bioactive androgens and spermatogenesis. These studies should provide important new information needed to develop an effective hormone-based male contraceptive, as well as provide substantial new insight into the physiological mechanisms through which T regulates spermatogenesis in men. The biological effects of androgens on spermatogenesis are mediated via the androgen receptor (AR) in Sertoli cells. The primary objective of Project II (Terry Brown) is to elucidate the molecular mechanisms that drive expression of the AR gene in Sertoli cells and to identify the specific transcription factors and their cis-acting regulatory elements that control the pubertal maturation dependent and adult stage-specific transcription of the AR gene. Project III (William Wright) focuses on paracrine regulation of spermatogenesis by examining the in vivo function of Sertoli cell growth factors, GDNF, FGF-2 and IGF-1, which have been implicated as involved in the control of stem spermatogonial replication and differentiation. Its central hypothesis is that differentiated germ cells, via feedback effects, regulate the expression by Sertoli cells of growth factors that, in turn, regulate the differentiation and replication of stem spermatogonia. Finally, we propose a Pilot Project (Paul Miller) that is based on our understanding that germ cell DNA is subject to damage and may be an important factor in male infertility. A rapid, simple analytical method to assess the level of oxidative DNA damage in germ cells will be developed using beacon aptamers, oligonucleotides that have the ability to bind ligands in a highly specific manner. These biosensors will be designed to measure oxidized nucleosides, 8-oxodeoxyadenosine and 8-oxodeoxyguanosine, in the DNA of sperm from infertile men.