Molecular mechanisms of endometrial progesterone resistance

子宫内膜黄体酮抵抗的分子机制

基本信息

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
项目类别：
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&apos 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

项目摘要

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。