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.

项目总结