# Role of REST in endometriosis-associated progesterone resistance

> **NIH NIH R21** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $229,500

## Abstract

Project Summary
 Endometriosis is a significant female disease characterized by infertility and pelvic pain in which
endometrial stromal and glandular tissue grow in ectopic locations. Several contributing factors such as poor
oocyte quality, impaired implantation and progesterone resistance have been implicated as contributing factors
to endometriosis-associated infertility, yet the precise mechanisms are poorly understood. Progesterone
resistance is thought to influence both the ectopic (endometriotic lesion) and eutopic endometrium. Altered
responsiveness of endometriotic lesion tissue is proposed to contribute to the survival of the ectopic tissue,
while inability of eutopic endometrium to adequately respond to progesterone is believed to contribute to the
infertility associated with the disease. Numerous studies have demonstrated that in women with
endometriosis, endometrial progesterone target genes are misexpressed. Several theories on the molecular
basis of progesterone resistance in endometriosis have been put forth including altered expression of
progesterone receptors (PGR)-A and PGR-B, as well as inflammation, genetics, and epigenetics. However, the
exact mechanism of this resistance has yet to be fully elucidated. Thus, there remains a critical gap in our
knowledge as to why endometrium (both eutopic and ectopic) from women with endometriosis exhibits altered
progesterone responsiveness.
 Preliminary findings in support of this application suggest that protein expression of the neuron-restrictive
silencer factor/RE1-silencing transcription factor, REST is absent/severely reduced in both eutopic and ectopic
endometriotic lesion tissue in women with endometriosis. REST is a transcriptional repressor that primarily
represses neuronal gene expression in non-neuronal tissues, but can also act as an enhancer of gene
transcription and may function in a similar capacity for progesterone action in endometrial tissue. The current
study will expand upon our preliminary findings and test the hypothesis that loss of REST expression in eutopic
and ectopic endometrium leads to an inability to adequately respond to progesterone, which respectively leads
to an inability to produce offspring (infertility) and allows persistence of endometriotic lesion survival. This
hypothesis will be tested under two specific aims which will: 1) delineate the REST-progesterone pathway in
ectopic and eutopic endometrium and verify the role of REST in regulation of progesterone target genes, and
2) demonstrate functional necessity of REST in regulation of progesterone responsiveness in endometriosis-
associated infertility and pain as well as stromal to epithelial cell to cell signaling. Outcomes from this study
will provide new insight into the role of REST as a mediator of progesterone action and will lead to identification
of novel REST/progesterone targets which may be serve as future therapeutic targets for endometriosis
treatment.

## Key facts

- **NIH application ID:** 9979351
- **Project number:** 1R21HD099364-01A1
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Warren B Nothnick
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $229,500
- **Award type:** 1
- **Project period:** 2020-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979351

## Citation

> US National Institutes of Health, RePORTER application 9979351, Role of REST in endometriosis-associated progesterone resistance (1R21HD099364-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9979351. Licensed CC0.

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