Indentification of Male Contraceptive Lead Compounds

描述：(申请人提供)本项目的长期目标是 鉴定用于男性避孕药开发的先导化合物。这个 项目利用：1)阻断减数分裂的观察 精子发生中的重组导致发育中的细胞凋亡 精母细胞，因此不育，2)酵母的高度同源性 和哺乳动物减数分裂重组蛋白，3)观察到许多 参与基本细胞功能的哺乳动物基因可以在功能上 替代同源酵母菌基因；4)发展简单 用哺乳动物基因代替酵母的方法，以及5)发展 用于高通量筛选小分子间相互作用的简单方法 执行基本功能的化合物和特定的哺乳动物基因 放在酵母里。在这个第一阶段的应用中，我们建议替换五个基因 与人类同系物进行减数分裂重组所需的酵母。 人类减数分裂重组基因的鉴定 替换酵母同系物将为第二阶段拨款提供平台。在……里面 第二阶段，我们将进行高通量筛选，以确定 阻断人类减数分裂基因的功能。这些化合物将是候选化合物 男性避孕药，有可能可逆地阻断 精子发生。 建议的商业应用： 多年来的研究都未能生产出男性避孕药。大多数努力都集中在基于激素的方法上。该项目旨在确定应该以不太容易产生副作用的方式阻止精子发生的化合物家族，这些副作用阻碍了有效男性避孕药的开发。三分之一的夫妇目前使用基于男性的避孕方法。市场研究表明，人们对男性避孕药有着广泛的兴趣。

DESCRIPTION: (provided by applicant) The long-term objective of this project is to identify lead compounds for the development of male contraceptive drugs. The project takes advantage of: 1) the observation that blocking meiotic recombination in spermatogenesis leads to apoptosis of the developing spermatocytes, and therefore sterility, 2) the high degree of homology of yeast and mammalian meiotic recombination proteins, 3) the observation that many mammalian genes involved in basic cellular functions can functionally substitute for the cognate yeast genes, and 4) the development of simple methods for replacement of yeast with mammalian genes, and 5) the development of simple methods for high throughput screening for interactions between small compounds and specific mammalians genes that are performing essential functions in yeast. In this Phase I applications we propose to replace five genes of yeast that are required for meiotic recombination with their human homologs. Identification of human meiotic recombination genes that can functionally replace the yeast homologs will provide a platform for a Phase II grant. In Phase II, we would perform high throughput screening to identify compounds that block function of the human meiotic genes. These compounds would be candidate male contraceptives, potentially capable of reversibly blocking spermatogenesis. PROPOSED COMMERCIAL APPLICATION: Years of research have failed to produce a male contraceptive drug. Most efforts have focused on hormone-based approaches. This project is designed to identify familes of compounds that should block spermatogenesis in ways less prone to the side effects that have thwarted the development of effective male contraceptives. One third of couples currently use male-based contraceptive approaches. Market research suggests there is broad interest in a male contraceptive drug.