Molecular mechanisms of endometrial progesterone resistance

子宫内膜黄体酮抵抗的分子机制

• 批准号: 10662676
• 负责人: Jae-Wook Jeong
• 金额: $ 46.95万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662676
• 关键词: Ablation; Animal Model; Biological Models; CXCL9 gene; Centers for Disease Control and Prevention (U.S.); Couples; Defect; Development; Diagnosis; Disease; ERBB2 gene; Endometrial; Endometrial Stromal Cell; Endometrium; Epithelial; Estrogens; Etiology; Female; Female infertility; Functional disorder; Genes; Genetic Models; Genetically Engineered Mouse; Human; Imaging Techniques; Impairment; Infertility; Knock-out; Mediating; Mediator of activation protein; Mitogens; Molecular; Morphology; Mus; Phenotype; Pregnancy; Problem Solving; Progesterone; Progesterone Receptors; Proto-Oncogenes; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Spontaneous abortion; Spouses; Testing; Tissues; Uterus; Woman; Women' s Health; Work; age group; aged; biomedical imaging; cost; early pregnancy loss; endometriosis-related infertility; experimental study; failure Implantation; hormone regulation; implantation; infertility treatment; mouse model; myometrium; natural Blastocyst Implantation; overexpression; population based; pregnancy failure; pregnant; reproductive; reproductive tract; response; success; trying to conceive; uterine receptivity

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.

项目概要 美国疾病控制与预防中心估计，大约有 610 万人不孕不育。 美国有15-44岁女性配偶的夫妇，约占国内已婚夫妇的6.7% 该年龄组的人口基数。大约 15% 的已知女性也会在 20 周前流产 妊娠失败，超过 75% 的妊娠失败涉及着床缺陷。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 抵抗意味着 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 具有非接受性子宫内膜的女性的子宫内膜。然而，P4 信号到底如何变成 非容受性子宫内膜有缺陷尚不清楚。 MIG-6 作为关键的 P4 信号传导介质来抑制 E2 介导的人类和小鼠子宫内膜上皮增殖。我们假设 Mig-6 子宫内膜中 ErbB2 过度表达和 P4 失调导致子宫内膜 P4 抵抗 子宫内膜基质细胞中的信号传导。在本提案中，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缺失在着床失败中的病理生理学作用； 2）Erbb2的影响 消融治疗 Mig-6 缺乏症女性不孕症。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 缺失在植入失败中的作用，并测试 Erbb2 靶向治疗 子宫内膜P4抵抗并恢复着床。我们的结果将增强我们对生殖的理解 病理生理学以及能够制定更有效的诊断和策略策略 治疗不孕症。