Control of Gamete Transport and Fertilization

我们在这项提案中的目标是研究一种新的女性避孕策略， 选择性雌激素受体调节剂（Selective Estrogen Receptor Modulators，SERM）SERMs是选择性地 调节各种组织中的雌激素作用。雌激素的作用是正常的生殖功能所必需的。 道组织这些功能包括：将精子运送到输卵管中的受精部位 输卵管;排卵后输卵管对卵母细胞的捕获;将发育中的胚胎运输到 子宫;以及胚胎植入子宫内膜。我们假设抗雌激素药物 针对生殖道的SERM治疗将导致精子/卵母细胞的选择性阻断 运输和受精。这种可能性的证据来自我们的观察， 给药一种新的非甾体SERM，ZK-SERM（Schering AG）阻断了雌激素在 恒河猴生殖道，导致宫颈和子宫内膜粘膜萎缩，和 抑制输卵管纤毛和分泌。为了检验这一假设，我们在具体目标1中提出， 检查ZK-SERM（我们的原型SERM）治疗是否会破坏配子运输和/或 猕猴的受精过程。在其他实验中，我们将检查形态学，生物化学和 生殖道内可能参与配子转运改变的分子终点， 受精我们进一步假设，选择性阻断雌激素作用的SERM，如ZK-SERM， 生殖道，可以提供一组有前途的化合物用于避孕。在Aim Specific 2中，我们 建议证明SERM治疗将在一个周期内阻断食蟹猴的生育能力。 通过ONPRC非人灵长类避孕药核心进行避孕试验。然后我们将评估 基于SERM的避孕效果的可逆性。在具体目标3中，我们将评估长期影响 SERM治疗对卵巢功能、月经周期、骨量和盆底结缔组织的影响。 这项研究，“在一天结束时”将提供一个明确的评估避孕的潜力， 针对生殖道的选择性抗雌激素SERM疗法。我们将有一个强烈的理解 抗雌激素SERM治疗对配子运输和生殖道功能的影响。在 此外，我们将有关于SERM治疗安全性的数据。这些数据将为新的研究提供基础 在未来的研究中，SERM的作用机制“下游”的雌激素受体-配体相互作用。

Our goal in this proposal is to investigate a novel strategy for female contraception that utilizes a new class of drugs, the Selective Estrogen Receptor Modulators (SERMs). SERMs are compounds that selectively regulate estrogen action in various tissues. Estrogen action is required for normal function of reproductive tract tissues. These functions include: the transport of spermatozoa to the site of fertilization in the fallopian tube; the capture of the oocyte by the fallopian tube after ovulation; the transport of the developing embryo to the uterus; and implantation of the embryo into the endometrium. Our hypothesis is that anti-estrogenic SERM therapy, targeting the reproductive tract, will result in a selective blockade of spermatozoa/oocyte transport and hence fertilization. Evidence for this possibility emanates from our observation that daily administration of a novel nonsteroidal SERM, ZK-SERM (Schering AG) blocked estrogen action in the rhesus macaque reproductive tract, resulting in atrophy of the cervical and endometrial mucosa, and suppression of oviductal ciliation and secretion. To test this hypothesis, we propose in Specific Aim 1 to examine whether therapy with ZK-SERM, our prototype SERM, will disrupt gamete transport and or fertilization in rhesus macaques. In additional experiments, we will examine morphological, biochemical and molecular endpoints within the reproductive tract that may participate in altered gamete transport and fertilization. We further hypothesize that SERMs, like ZK-SERM, that selectively block estrogen action in the reproductive tract, can provide a promising group of compounds for contraception. In Specific Aim 2 we propose to demonstrate that SERM therapy will block fertility in cynomologus macaques during a contraceptive trial through the ONPRC Nonhuman Primate Contraceptive Core. We will then assess the reversibility of the SERM-based contraceptive effect. In Specific Aim 3 we will assess the long-term effects of SERM treatment on ovarian function, menstrual cyclicity, bone mass and pelvic floor connective tissues. This research, "at the end of the day" will provide a definitive assessment of the contraceptive potential of selective antiestrogenic SERM therapy targeting the reproductive tract. We will have a strong understanding of the effects of antiestrogenic SERM therapy on gamete transport and reproductive tract functions. In addition we will have data on the safety of SERM therapy. These data will provide a basis for new studies on the mechanisms of SERM action "down stream" of estrogen receptor-ligand interactions in future studies.