Interdisciplinary Center for Male Contraceptive Research and Drug Development

说明（由申请人提供）：世界卫生组织（世卫组织）的统计数据显示，全世界每年发生1.22亿次计划怀孕。然而，尽管有许多不同的女性避孕方法和避孕套，另有8700万次意外怀孕（占所有怀孕的42%），4600万次怀孕因堕胎而终止。因此，美国国立卫生研究院、医学研究所和世卫组织已将开发新型可逆口服男性避孕药确定为解决这一全球生殖健康问题所需的一项重大进展。拟建的多机构U54“男性避孕药研究与药物开发跨学科中心”的目的是开发新的非激素男性避孕药。该中心研究项目的主要目标是使用已证明成功的跨学科方法，为美国国立卫生研究院提供用于药物开发的新型避孕药物。这将通过一个高度互动和协作的研究项目小组来完成：1)研究一组对精子发生、精子发生和精子功能至关重要的独特蛋白质靶点；2)通过我们最有前途的新型避孕药中新发现的男性避孕靶点，确定新的和替代的化学结构。具体研究项目有：

DESCRIPTION (provided by applicant): World Health Organization (WHO) statistics show that 122 million planned pregnancies occur worldwide per year. Yet, in spite of the availability of many different female contraceptive methods and condoms, an additional 87 million pregnancies are unintended (representing 42% of all pregnancies), and 46 million pregnancies terminated by abortion. Thus, the development of novel reversible oral male contraceptive agents has been identified as a major advance needed to address this worldwide reproductive health issue by the NIH, Institute of Medicine, and WHO. The purpose of the proposed multi-institutional U54 "Inter- disciplinary Center for Male Contraceptive Research and Drug Development" is to develop new non-hormonal male contraceptive agents. The Prime Objective of the research program of this center, using proven successful interdisciplinary approaches, will be to provide NIH with new and novel contraceptive agents for drug development. This will be accomplished by a highly interactive and collaborative group of research projects by 1) investigating a set of unique protein targets that are critical for spermatogenesis, spermiogenesis, and sperm function, and 2) identifying novel and alternative chemical structures that act via the newly discovered male contraceptive targets of our most promising new contraceptive agents. The specific research projects are: Research Project I: Mechanisms and novel male contraceptive agents that target Hsp90B and elongation factor-1a. Joseph S. Tash, Ph.D., PI Research Project II: Cardenolides inhibition of the sperm Na,K-ATPase a4 isoform as contraceptive agent Gustavo Blanco, Ph.D., PI, Research Project III: Small molecule inhibitors of Dmrtl-regulated target genes as male contraceptive agents Leslie Heckert, Ph.D., PI, Research Project IV: Sperm protein tyrosine kinases as targets for small molecule contraceptives William Kinsey, Ph.D., PI The research program includes a New Investigator Development Program that will foster and support new scientists involved in research to develop new male contraceptive agents. The research program is supported by a strong and highly interactive set of Core Units including an Administrative Core, Drug Discovery, Design & Synthesis Core, Drug Development Core, and Imaging Core. The scientists involved in the research projects and cores of this proposed center have a record of success in providing NIH with highly promising reversible non-hormonal male contraceptive agents that are already under drug development in collaboration with NIH. The research program in this center will expand this success into new protein targets involved in regulation of male fertility that will be exploited by cutting edge drug discovery and design approaches for generation of new classes of non-hormonal chemical structures as male contraceptive agents.