# Molecular Mechanisms Regulating Uterus Development

> **NIH NIH R37** · UNIVERSITY OF MISSOURI-COLUMBIA · 2024 · $657,027

## Abstract

Project Abstract
Infertility and pregnancy loss are common health disorders affecting women. Our long-term research goal is to define
critical physiological and genetic pathways that regulate uterine development, function, and regeneration to diagnose,
treat, and prevent infertility and associated uterine disorders and disease. This application is specifically focused on
the glands of the uterus that are characteristic features of all uteri and critical for pregnancy. Pregnancy loss is the
most common complication of human gestation, and recurrent pregnancy loss and infertility are observed in uterine
gland knockout animal models. The pioneer transcription factor forkhead box A2 (FOXA2), exclusively expressed in
the glands of the mouse and human uterus, plays a pivotal role in uterine gland development and function, and is
implicated in a variety of uterine pathologies (infertility, adenomyosis, endometriosis, adenocarcinoma). However,
our understanding of uterine epithelial development, FOXA2 biology, and gland morphogenesis is very incomplete.
Central hypotheses of this application are that: (1) intrinsic genetic and epigenetic mechanisms govern epithelial
specification, bifurcation, differentiation, and morphogenesis in the neonatal mouse uterus; (2) glandular epithelium
lineage bifurcation requires Foxa2 gene activation via chromatin remodeling; and (3) FOXA2 activates gene
regulatory networks and cellular pathways critical for adenogenesis in the uterus. A team of exceptional investigators
with complementary and substantial expertise in developmental biology, functional genomics, and bioinformatics will
address that hypothesis by conducting a collaborative research project. Guided by strong published and preliminary
data, two specific aims are proposed: (1) understanding molecular mechanisms regulating epithelial specification and
Foxa2 expression in the developing uterus; and (2) FOXA2 regulation of adenogenesis in the developing uterus. The
proposed systems biology approach will integrate in vivo and in vitro studies utilizing mouse genetic models, single-
cell profiling of chromatin accessibility and gene expression (multiome), advanced bioinformatics and deep learning
techniques, as well as mechanistic studies of mouse and human endometrial organoids. This approach will decipher
essential conserved factors, gene regulatory networks, and cellular pathways governing epithelial development and
Foxa2 regulation and biological function. The proposed aims are conceptually and technically innovative and together
will have a broad impact on the field by filling a substantial gap in our fundamental knowledge of uterine development
and biology. This application specifically addresses early pregnancy loss and the genetic basis of idiopathic female
infertility, which aligns with the research priorities of the Fertility and Infertility Branch of the NICHD. Ultimately,
an increased understanding of uterine gland biology will facilitate diagnosis, prev...

## Key facts

- **NIH application ID:** 10853615
- **Project number:** 1R37HD114609-01
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** THOMAS E SPENCER
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $657,027
- **Award type:** 1
- **Project period:** 2024-07-19 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853615

## Citation

> US National Institutes of Health, RePORTER application 10853615, Molecular Mechanisms Regulating Uterus Development (1R37HD114609-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10853615. Licensed CC0.

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