PDE3 Inhibitors: Selective Blockers of Oocyte Maturation

PDE3 抑制剂：卵母细胞成熟的选择性阻断剂

• 批准号: 6824674
• 负责人: JEFFREY T. JENSEN
• 金额: $ 32.2万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6824674
• 关键词: 3' 5' cyclic nucleotide phosphodiesterase; Macaca mulatta; contraceptives; corpus luteum; drug discovery /isolation; drug screening /evaluation; egg /ovum; fertilization; gene expression; in situ hybridization; isozymes; laparoscopy; meiosis; menstrual cycle; oogenesis; ovulation; pharmacokinetics; phosphodiesterase inhibitors; protein isoforms; protein localization

DESCRIPTION (provided by applicant): The need for contraception has never been greater, as evidenced by a world population of over 6 billion, and greater than one billion young people currently in the prime reproductive years. Overpopulation is a pernicious public health affliction that ravages infrastructure and limits the achievement of hard fought gains in overall health status by threatening the basic infrastructure of humanity. Contraception also provides significant preventative health benefits by reducing unintended pregnancy, abortions, and unwanted births. As side effects, access, and cultural or moral objections limit the universal acceptance of current methods, research into novel contraceptives is warranted. The purpose of this grant is to explore the hypotheses that selective expression of phosphodiesterase (POE) isoforms exists in the primate ovary, that selective blockade of PDE3 can be exploited to prevent spontaneous and gonadotropin induced oocyte maturation, and that chronic treatment with a PDE3 inhibitor can prevent pregnancy in primates without affecting menstrual cyclicity or luteal function. The Specific Aims are to: (1) Describe the basic biology of PDE expression in the primate ovary. The goal of this aim is to characterize the PDE isoenzymes expressed in the macaque ovary. An additional goal will be to test novel PDE3 inhibitors for their ability to prevent spontaneous resumption of meiosis in vitro to learn if greater selectivity or potency can be achieved. (2) Determine if PDE3 inhibitors prevent oocyte maturation, but not ovulation and function of the corpus luteum in rhesus monkeys undergoing controlled ovarian stimulation (COS) protocols or during natural cycles in vivo. The goals of this aim will be to document that oocyte inhibition can be effectively and selectively achieved in vivo, and to investigate the systemic toxicity of PDE3 inhibitors at pharmacologically active dosages in vivo. 3) Determine whether PDE3 inhibitors function as contraceptive agents in regularly cycling rhesus monkeys in paired mating situations. The goal of this aim is to document the efficacy and practicality of systemic administration of a PDE3 inhibitor as a potential contraceptive through longer-term observation. Experimental designs will include: characterization of PDE gene products (mRNA and protein) in somatic and germ cells from ovarian tissue (Aim 1), in vitro incubation of immature oocytes and granulosa cells with PDE3 inhibitors (Aim 1), in vivo administration of a PDE3 inhibitor to monkeys during COS and spontaneous menstrual cycles, followed by follicular aspiration to assess oocyte maturation and fertilizability in vitro, plus endocrine and toxicity measurements (Aim 2), and chronic administration of a PDE 3 inhibitor to fertile females caged with fertile males to assess contraceptive efficacy and long term toxicity (Aim 3). This approach is expected to provide a foundation for future Phase 1 trials of PDE3 inhibitors in humans.

描述（由申请人提供）：避孕的需求从未有所更大，这是世界人口超过60亿人口所证明的，目前正处于主要生殖年中的十亿年轻人。人口过多是一种有害的公共卫生苦难，它破坏了基础设施，并通过威胁人类的基本基础设施来限制艰苦的整体健康状况中的艰难得益。避孕还可以通过减少意外怀孕，流产和不必要的出生来提供重大的预防健康益处。随着副作用，访问以及文化或道德异议限制了当前方法的普遍接受，因此有必要研究对新型避孕方法的研究。这笔赠款的目的是探索在灵长类卵巢中存在选择性表达磷酸二酯酶（POE）的选择性表达，可以利用PDE3的选择性阻断以防止自发性和促性腺激素可防止卵母细胞的自发性和促性蛋白诱导的卵母细胞的治疗，并导致pde3的耐药性或抑制作用。 功能。具体目的是：（1）描述灵长类动物卵巢中PDE表达的基本生物学。该目标的目的是表征在猕猴卵巢中表达的PDE同工酶。另一个目标是测试新型PDE3抑制剂，以防止在体外自发恢复减数分裂以了解是否可以提高选择性或效力。 （2）确定PDE3抑制剂是否可以防止卵母细胞的成熟，但不能防止luteum luteum在恒河猴中使用受控卵巢刺激（COS）方案或体内天然周期期间的排卵和功能。该目标的目标是记录卵母细胞抑制作用可以在体内有效，有选择地实现，并研究体内药理学活性剂量的PDE3抑制剂的系统性毒性。 3）确定PDE3抑制剂是否在配对的交配情况下定期循环恒河猴中的避孕药是否起避孕剂的作用。该目的的目的是记录系统给药PDE3抑制剂的功效和实用性，作为通过长期观察的潜在避孕药具。 Experimental designs will include: characterization of PDE gene products (mRNA and protein) in somatic and germ cells from ovarian tissue (Aim 1), in vitro incubation of immature oocytes and granulosa cells with PDE3 inhibitors (Aim 1), in vivo administration of a PDE3 inhibitor to monkeys during COS and spontaneous menstrual cycles, followed by follicular aspiration to assess卵母细胞成熟和体外的肥沃性，以及内分泌和毒性测量值（AIM 2），以及长期给予PDE 3抑制剂，以肥沃的雌性与肥沃的雄性饲养以评估避孕功效和长期毒性（AIM 3）。预计这种方法将为人类PDE3抑制剂的未来1阶段试验提供基础。