# Molecular mechanisms of endometrial progesterone resistance

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2021 · $514,696

## Abstract

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.

## Key facts

- **NIH application ID:** 10229616
- **Project number:** 5R01HD101243-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Jae-Wook Jeong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $514,696
- **Award type:** 5
- **Project period:** 2020-08-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229616

## Citation

> US National Institutes of Health, RePORTER application 10229616, Molecular mechanisms of endometrial progesterone resistance (5R01HD101243-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10229616. Licensed CC0.

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