# Regulation of Endometriotic Lesion Development by NOTCH1

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2021 · $547,003

## Abstract

Project Summary
Endometriosis is a chronic, estrogen-dependent gynecological disorder affecting 10-15% of women of
reproductive age resulting in pelvic pain and infertility. It is characterized by the presence of endometrial tissue
outside the uterus, predominantly in the pelvic peritoneum. The activity of endometriotic lesions or implants, and
the development of subsequent adhesions, is the likely causes of the disease symptoms. Lesion development
is difficult to study in women with endometriosis because of the significant delays in diagnosis. In the past 20
years we have developed the baboon as an appropriate model to better examine the establishment and
progression of endometriotic lesions. Understanding the mechanisms that regulate the development and
progression of ectopic lesions at the onset of the disease will result in new opportunities for targeted therapies
to prevent and/or treat endometriosis. The Notch family of transmembrane receptors (NOTCH1-4) transduces
extracellular signals responsible for cell survival, cell-to-cell communication, and differentiation. Our Central
Hypothesis is that IL-6, which is present in the inflammatory peritoneal environment induces the expression of
the E-protein transcription factors E2A and HEB, which in turn upregulates NOTCH1 expression by directly
binding to the NOTCH1 promoter. The induction of NOTCH1 promotes endometriotic lesion development by
controlling cell proliferation, invasion and EMT. In this proposal we will utilize our innovative engineered mouse
models, the established baboon endometriosis model together with well characterized human tissues to
understand how NOTCH1 is induced and how the induction and upregulation of NOTCH1 contributes to
endometriotic lesion development. Specific Aim 1 will focus on the molecular mechanisms by which IL-6, in the
context of endometriosis, regulates the expression of E-protein transcription factors (E2A and HEB) to induce
NOTCH1 in vitro and in vivo and determine the molecular mechanisms by which NOTCH1 activates signaling
pathways that contribute to endometriotic lesion development. Specific Aim 2 will focus on functional studies
using 3-D and organoid cell culture models and our unique fluorescence-tagged NOTCH1 gain of function and
loss of function mouse models to dissect the molecular mechanisms and pathological consequences by which
increased NOTCH1 expression in endometriotic tissues regulates cell proliferation and induces EMT to enhance
migration and invasion. Specific Aim 3 will use both engineered mouse models and the baboon endometriosis
model for targeted delivery of a dominant negative Mastermind-like (DN-MAML) peptide (SAHM1) using
fluorescently labeled nanoparticles to inhibit NOTCH1 signaling as a novel therapeutic approach to inhibit the
pathologic processes associated with the disease. The outcomes of these studies will enhance our
understanding of the etiology and pathophysiology of endometriotic lesion development and elucidate nove...

## Key facts

- **NIH application ID:** 10120045
- **Project number:** 1R01HD099090-01A1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Asgerally T. Fazleabas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $547,003
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120045

## Citation

> US National Institutes of Health, RePORTER application 10120045, Regulation of Endometriotic Lesion Development by NOTCH1 (1R01HD099090-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120045. Licensed CC0.

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