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.

项目摘要疾病控制与预防中心估计有大约610万不育在美国，有一对15-44岁的女配偶的夫妻，约占家庭已婚夫妇的6.7％该年龄段的人口基础。 20周之前的流产也发生在大约15％的已知怀孕，超过75％的妊娠涉及植入缺陷。为了解决这些问题，我们必须了解子宫接受性和植入的机制，以开发出更好的治疗方法目前遥不可及。子宫内膜上皮和基质室经历动态分子和形态学的变化以准备植入和发育。子宫内膜P4电阻意味着目标组织对生物可利用P4的反应性降低，并且在这种情况下看到了这种受损的P4反应妇女的子宫内膜非受毒性子宫内膜。但是，确切的P4信号传导如何变为在非受体子宫内膜中有缺陷尚不清楚。 MIG-6充当关键的P4信号介质抑制 E2介导的人和小鼠子宫内膜中的上皮增殖。我们假设MIG-6 损失会导致子宫内膜中ERBB2过表达的子宫内膜P4耐药性和失调P4 子宫内膜基质细胞中的信号传导。在此提案中，我们的目标是确定MIG-6在子宫及其在子宫内膜P4抗性和不育症中的失调。我们的具体目标是针对的理解：1）MIG-6损失在植入衰竭中的病理生理作用； 2）ERBB2的效果 Mig-6缺乏症的女性不孕症消融。使用我们的鼠标模型和生物医学成像技术，我们将确定MIG-6损失在植入失败和测试ERBB2靶向治疗中的作用子宫内膜P4抗性和恢复植入。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策略不孕症的治疗。