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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.

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。项目一（巴里Zirkin和乔纳森Jarow）地址的生物机制，解释为什么只有一些男性谁接受激素避孕成为无精子症。将研究对睾酮（T）避孕反应的自然发生的种族差异，以解决这一生物学问题。我们将比较亚洲和高加索男性在接受基于避孕药的T避孕剂量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。这些研究应该提供重要的新信息，需要开发一种有效的基于避孕药的男性避孕药，以及提供大量的新的洞察力的生理机制，通过T调节男性精子发生。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）的主要目的是阐明支持细胞中AR基因表达的分子机制，并鉴定控制AR基因的青春期成熟依赖性和成人阶段特异性转录的特异性转录因子及其顺式作用调控元件。项目III（William Wright）通过检查支持细胞生长因子、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控制干精原细胞复制和分化。其中心假设是，分化的生殖细胞，通过反馈效应，调节支持细胞的生长因子的表达，反过来，调节干精原细胞的分化和复制。最后，我们提出了一个试点项目（保罗米勒），这是基于我们的理解，生殖细胞DNA受到损害，可能是一个重要因素，在男性不育。一种快速，简单的分析方法，以评估在生殖细胞中的氧化DNA损伤的水平将开发使用信标适体，寡核苷酸，具有结合配体的能力，在一个高度特异性的方式。这些生物传感器将被设计用于测量不育男性精子DNA中的氧化核苷，8-氧代脱氧腺苷和8-氧代脱氧鸟苷。