Interdisciplinary Center for Male Contraceptive Research and Drug Development

描述(由申请人提供)：世界卫生组织(WHO)的统计数据显示，全球每年发生1.22亿例计划怀孕。然而，尽管有许多不同的女性避孕方法和避孕套可用，还有8700万人是意外怀孕(占所有怀孕的42%)，4600万人因堕胎而终止妊娠。因此，新型可逆口服男性避孕药的开发已被NIH、医学研究所和世卫组织确定为解决这一全球生殖健康问题所需的重大进展。拟成立的多机构U54“男性避孕研究和药物开发跨学科中心”的目的是开发新的非荷尔蒙男性避孕药。该中心研究计划的主要目标是利用已被证明成功的跨学科方法，为NIH提供用于药物开发的新的和新型的避孕药。这将通过一个高度互动和协作的研究项目小组来完成，方法是1)调查一组对精子发生、精子发生和精子功能至关重要的独特蛋白质靶点，以及2)确定通过我们最有希望的新避孕药的新发现的男性避孕靶发挥作用的新颖和替代的化学结构。具体的研究项目是：研究项目I：针对Hsp90p和延伸因子-1a的机制和新型男性避孕药。约瑟夫·S·塔什，博士，PI研究项目II：Cardenoldes抑制精子Na，K-ATPase A4亚型作为避孕剂Gustavo Blanco，Ph.D.，Pi，研究项目III：作为男性避孕剂的Dmrtl调节目标基因的小分子抑制剂Leslie Heckert，Ph.D.，PI，研究项目IV：精子蛋白酪氨酸激酶作为小分子避孕药的靶标William Kinsey，Ph.D.，Pi研究计划包括一个新的研究者开发计划，该计划将培养和支持参与研究的新科学家开发新的男性避孕剂。该研究计划得到了一套强大和高度互动的核心单位的支持，其中包括管理核心、药物发现、设计和合成核心、药物开发核心和成像核心。参与这个拟建中心的研究项目和核心的科学家们已经成功地为NIH提供了非常有前途的可逆非激素男性避孕药，这些药物已经在与NIH合作进行药物开发。该中心的研究计划将把这一成功扩展到涉及调节男性生育能力的新蛋白质靶标，这些靶标将被尖端药物发现和设计方法所利用，以产生作为男性避孕剂的新型非激素化学结构。

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 Hsp90p and elongation factor-la. 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.