Hormonal and Paracrine Regulation of Spermatogenesis

精子发生的激素和旁分泌调节

基本信息

批准号：
7873004
负责人：
BARRY R ZIRKIN
金额：
$ 95.81万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-03 至 2012-03-31
项目状态：
已结题

项目摘要

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.

该应用的重点是人类和啮齿动物中精子发生的激素和旁分泌调节。项目I（Barry Zirkin和Jonathan Jarow）解决了生物学机制，这些机制解释了为什么只有一些接受激素避孕的男性才能成为Azoospermic。将研究对基于睾丸激素（T）的避孕的自然发生的种族差异，以解决这一生物学问题。我们将在接受基于激素的避孕药剂量之前和之后比较亚洲和高加索人的生物活性雄激素的静脉内浓度，并将确定HCG [人类绒毛膜促性腺激素]诱导的内部性生物活性雌激素和精子生成之间的定量关系。这些研究应提供开发有效的基于激素的男性避孕药所需的重要新信息，并提供对T调节男性精子发生的生理机制的大量新见解。雄激素对精子发生的生物学作用是通过Sertoli细胞中的雄激素受体（AR）介导的。项目II（Terry Brown）的主要目的是阐明驱动Sertoli细胞中AR基因表达的分子机制，并确定控制依赖于青春期成熟的特定转录因子及其顺式作用调节元件，这些元件依赖于青春期成熟和AR基因的成人阶段特异性转录。 III（William Wright）通过检查Sertoli细胞生长因子的体内功能GDNF，FGF-2和IGF-1的体内功能，重点介绍了精子发生的旁分泌调节，这些功能与控制茎的精子复制和差异有关。它的中心假设是，通过反馈效应分化的生殖细胞调节了生长因子的Sertoli细胞的表达，从而调节了茎精子的分化和复制。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受到损害，可能是男性不育的重要因素。一种快速，简单的分析方法来评估生殖细胞中氧化性DNA损伤水平，将使用信标适体，具有高度特异性方式结合配体的能力的寡核苷酸。这些生物传感器将被设计为在来自不育男性的精子中测量氧化核苷，8-氧化氧化腺苷和8-氧化氧化鸟苷。