# Molecular mechanisms of gap junction promotion of lesion formation in Endometriosis

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $429,046

## Abstract

Invasive cell behavior is a component of normal (blastocyst implantation, extravasation) and pathogenic 
processes (metastasis, endometriosis), and is initiated by heterotypic contacts between cells. There is strong 
evidence, particularly in metastatic cancer, that gap junction (GJ) mediated intercellular coupling (GJIC) between 
the invading cells and target tissue plays a critical role. Yet gap junctions have not been studied in the most 
common invasive pathogenesis – endometriosis. Endometriosis is thought to arise through retrograde 
menstruation of endometrial tissue to the peritoneum (occurring in most women), but there is active debate as 
to whether the disease is due to changes in the endometrium (the “seed”) or a permissive peritoneal environment 
(the “soil”). Project 1 demonstrated a striking downregulation of GJ genes in stromal cells (ESCs), and an inverse 
upregulation in epithelial cells (EECs) that follows the progression of the disease, and could serve as a diagnostic. 
Here we show that ESCs from endometriosis patients are unique in showing a large induction of GJIC upon 
interaction with peritoneal mesothelial cells (PMCs). This heterotypic GJIC was critical for the ESC invasiveness 
by inducing a disruption of the barrier function of the mesothelium. Conversely, PMCs also selectively affect 
ESCs from endometriosis patients by triggering Cx43 assembly into GJs, and by inducing a Mesenchymal to 
Epithelial Transition (MET). These results lend strong support the “seed” hypothesis. 
 The current proposal builds on these results within the collaborative environment of a P01 that will allow a 
comprehensive analysis of how intercellular interactions in endometriosis lead to lesion formation. This will 
include understanding: (a) How GJ, and related adhesive genes, are regulated in endometriosis (Project 1); (b) 
how ESCs and PMCs initially recognize and stably adhere to one another (Project 3), leading to GJ formation, 
and; (c) how these GJs induce both modification of the PMC barrier function and promote ESC invasive behavior 
(Project 2). The goals of Project 2 will be achieved through three aims: 
Aim 1: Establish what functions of Cx43 are important for initiating invasiveness (i.e. GJIC, hemichannels, 
protein scaffolds) (1.1) and identify the molecular changes induced in PMCs that disrupt barrier function (1.2).
Aim 2: Explore the converse effects of PMCs on endometriosis-derived ESCs by assessing if HA-CD44 
interactions (Proj. 3), or other signals, induce heterotypic GJ formation (2.1), exploring the dependence of 
molecular changes induced in ESCs by PMCs (e.g. MET) on heterotypic GJIC (2.2), and whether PMCs derived 
from the peritoneum of control or endometriosis patients (the “soil”) differ in the effects they elicit (2.3).
Aim 3: Validate the in vitro models for relevance to endometriotic lesion formation in a syngeneic mouse 
transplant model, exploring the roles of Cx43 in both endometrium (3.1) and peritoneal me...

## Key facts

- **NIH application ID:** 10886714
- **Project number:** 5R01HD109027-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** BRUCE J NICHOLSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,046
- **Award type:** 5
- **Project period:** 2021-09-17 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886714

## Citation

> US National Institutes of Health, RePORTER application 10886714, Molecular mechanisms of gap junction promotion of lesion formation in Endometriosis (5R01HD109027-04). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10886714. Licensed CC0.

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