Functional Genomic Approach to Male Contraception

描述(申请人提供)：现代避孕方法的历史短得令人惊讶，主要是几种方法，如女性的口服避孕药或男性的身体屏障方法，如避孕套。尽管缺乏方法的选择，但研究表明，男性渴望在调节生育方面发挥更大的作用。过去的一些努力集中在男性避孕药的开发上，这些避孕药侧重于对精子发生的激素和免疫控制，但很少有研究专注于开发一种能够改变调节精子发生的关键基因的活动的男性避孕药。这就是我们概述的方法。这是一种及时的方法，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，我们已经在果蝇中发现了编码男性生育因子的基因，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基因敲除(KO)小鼠的表型来探索男性不育的机制。这项研究的目的是确定和表征参与调节男性生育能力的新的基因靶点，并为开发针对这些目标的男性避孕药奠定基础。我们将筛选小鼠ES基因陷阱细胞库，寻找通过比较基因组学分析确定的男性生殖基因，以产生扰乱保守的男性生育因子的小鼠KO突变体，并表征这些关键调控因子在精子产生和成熟中的作用，最终为避孕领域和生殖领域的研究人员提供男性生殖突变体资源。

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.