Functional Genomic Approach to Male Contraception

描述（由申请人提供）：现代避孕方法的历史出奇地短，主要是少数几种方法，如女性口服避孕药或男性使用避孕套等物理屏障方法。尽管缺乏可供选择的方法，但研究表明，男性渴望在调节生育方面发挥更大的作用。过去的一些研究集中在男性避孕药的开发上，主要集中在精子发生的激素和免疫控制上，但很少有研究集中在开发一种可以改变调节精子发生的关键基因活性的男性避孕药上。这是我们概述的方法。这是一个及时的方法，因为随着人类基因组计划和模式生物计划的完成，我们对可能控制精子发育的基因和蛋白质有了前所未有的了解。在我们的初步研究中，我们已经确定了果蝇中编码雄性生育因子的基因，在小鼠和人类中发现了同源基因，并开始通过检测不育突变果蝇和敲除（KO）小鼠的表型来探索雄性不育的机制。这项研究的目的是查明和描述与调节男性生育能力有关的新基因目标，并为针对这些目标研制男性避孕药具奠定基础。我们将在小鼠ES基因陷阱细胞文库中筛选通过比较基因组学分析发现的雄性生殖基因，生成破坏保守的雄性生殖因子的小鼠KO突变体，表征这些关键调控因子在精子产生和成熟过程中的作用，最终为避孕和生殖领域的研究人员提供雄性生殖突变体资源。

DESCRIPTION (provided by applicant): Modern contraceptive methods have a surprisingly short history and are dominated by a few methods such as the oral contraceptive pill for women or physical barrier methods such as condoms for men. In spite of the lack of choice of methods, studies show that men aspire to play a greater role in the regulation of fertility. Some effort in the past has been focused on development of male contraceptives, which focused on hormonal and immunological control of spermatogenesis, but few studies have focused on developing a male contraceptive that will alter the activity of key genes that regulate spermatogenesis. This is the approach that we outline. It is a timely approach, as with the completion of the human genome project and those of model organisms, we have unprecedented knowledge of the genes and proteins that are likely to govern the development of sperm. In our preliminary studies, we have identified genes that encode male fertility factors in Drosophila, discovered homologs in mice and humans, and begun to explore mechanisms of male infertility by examining the phenotypes of sterile mutant flies and knockout (KO) mice. The objectives of this research are to identify and to characterize novel gene targets involved in the regulation of male fertility and to lay the ground work for the development of male contraceptives against those targets. We will screen a mouse ES gene trap cell library for male reproductive genes identified through our comparative genomics analysis, to generate mouse KO mutants disrupting the conserved male fertility factors, to characterize the roles of those key regulators during sperm production and maturation, and finally to provide a resource of male reproductive mutants for researchers in the contraceptive field, as well as in the reproductive field.