Molecular mechanisms of endometrial progesterone resistance

项目摘要 疾病控制和预防中心估计，大约有610万不孕症患者， 在美国有15-44岁女性配偶的夫妇，这一比例约为6.7%， 这个年龄段的人口基数。20周前流产也发生在约15%的已知 怀孕，超过75%的失败怀孕涉及植入缺陷。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， 目前无法触及。子宫内膜的上皮和间质区室经历动态的分子调控， 和形态变化，为植入和发育做准备。子宫内膜P4抵抗意味着 靶组织对生物可利用的P4的反应性降低，并且这种受损的P4反应见于 非接受性子宫内膜妇女的子宫内膜。然而，P4信号是如何变成 非接受性子宫内膜的缺陷仍不清楚。β 2 -6作为一个关键的P4信号介质，抑制 E2介导的人和小鼠子宫内膜上皮细胞增殖。我们假设米格-6 ErbB 2在子宫内膜过度表达和P4失调导致子宫内膜P4抵抗 子宫内膜间质细胞中的信号传导。在本提案中，我们的目标是确定在全球范围内， 子宫及其在子宫内膜P4抵抗和不孕症中的失调。我们的具体目标是针对 理解：1）Erbb 2 -6缺失在着床失败中的病理生理作用; 2）Erbb 2 治疗Mig-6缺乏性女性不孕症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Erbb 2靶向治疗 子宫内膜P4抵抗和恢复种植。我们的研究结果将增强我们对生殖的理解， 病理生理学，以及使发展更有效的战略，诊断和 治疗不孕症。

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.