Molecular mechanisms of endometrial progesterone resistance

项目摘要 疾病控制和预防中心估计，大约有610万人不育 在美国，女性配偶年龄在15-44岁之间的夫妇，约占国内已婚夫妇的6.7% 该年龄段的人口基数。20周前流产也发生在约15%的已知病例中 怀孕，75%以上的失败妊娠涉及植入缺陷。为了解决这些问题，我们 必须了解子宫容受性和着床的机制，以开发更好的治疗方法， 目前遥不可及。子宫内膜的上皮室和间质室经历动态分子变化 和形态变化，为植入和发育做准备。子宫内膜P4耐药意味着 靶组织对生物可利用的P4的反应性降低，这种受损的P4反应见于 非接受型子宫内膜者的子宫内膜。然而，P4信号到底是如何变成的 非接受性子宫内膜的缺陷仍不清楚。MiG-6作为关键的P4信号媒介抑制 雌激素对人和小鼠子宫内膜上皮细胞增殖的影响。我们假设米格-6 丢失通过ErbB2在子宫内膜的过度表达和P4的失调而导致子宫内膜P4抵抗 子宫内膜间质细胞中的信号转导。在这项提案中，我们的目标是确定MIG-6在 子宫及其在子宫内膜P4抵抗和不孕症中的失调。我们的具体目标是 理解：1)MIG-6缺失在植入失败中的病理生理作用；2)ERBB2的作用 Mig-6缺乏症女性不孕症的消融治疗使用我们的小鼠模型和生物医学成像 技术，我们将确定Mig-6丢失在植入失败中的作用，并测试ERBB2靶向治疗 子宫内膜P4抵抗和复植。我们的结果将增强我们对生殖的理解 病理生理学，并使开发更有效的策略诊断和 不孕不育的治疗。

Project Summary The Centers for Disease Control and Prevention has estimated that there are approximately 6.1 million infertile couples with a female spouse aged 15-44 in the U.S., which is about 6.7% of the domestic married couple population base for that age group. Miscarriage before 20 weeks also occurs in about 15% of known pregnancies, and over 75% of failed pregnancies involve implantation defects. To solve these problems, we must understand the mechanisms of uterine receptivity and implantation to develop better treatments that may be currently out of reach. The endometrium's epithelial and stromal compartments undergo dynamic molecular and morphological changes to prepare for implantation and development. Endometrial P4 resistance implies a decreased responsiveness of target tissue to bioavailable P4, and such an impaired P4 response is seen in the endometrium of women with non-receptive endometrium. However, exactly how P4 signaling becomes defective in a non-receptive endometrium is still unclear. MIG-6 acts as a key P4 signaling mediator to inhibit E2-mediated epithelial proliferation in the endometrium of the human and mouse. We hypothesize that Mig-6 loss causes endometrial P4 resistance by ErbB2 overexpression in the endometrium and by dysregulating P4 signaling in endometrial stromal cells. In this proposal, our objective is to determine how MIG-6 functions in the uterus and how it is dysregulated in endometrial P4 resistance and infertility. Our Specific Aims are directed at understanding: 1) the pathophysiological role of MIG-6 loss in implantation failure; and 2) the effect of Erbb2 ablation on female infertility with Mig-6 deficiency. Using our mouse models and biomedical imaging techniques, we will determine the role of Mig-6 loss in implantation failure and test Erbb2 targeting to treat endometrial P4 resistance and restore implantation. Our results will enhance our understanding of reproductive pathophysiology as well as enable the development of more effective strategies for the diagnosis and treatment of infertility.