# Understanding the functional role of fibroid subtype mutations for drug discovery

> **NIH NIH K99** · HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES · 2024 · $107,860

## Abstract

PROJECT SUMMARY/ABSTRACT
Research Project: Uterine fibroids are the most common benign tumors in women of reproductive age. The
economic impact of symptomatic uterine fibroids in the United State is estimated to be nearly $34 billion annually.
The incidence of these tumors is age and race dependent and has been estimated to be detected in up to 80%
of women by age fifty. Genetic mutation appears to contribute to fibroid tumorigenesis, and two altered genes,
the high mobility group AT-hook 2 (HMGA2) and mediator complex subunit 12 (MED12), are observed in
approximately 85% of all fibroids. A major gap in knowledge is to define the functional role of these mutations in
myometrium and determine if they are sufficient to induce a fibroid phenotype. Studies have described the
transcriptomic and methylation profiles of uterine fibroids showing a strong divergence between subtypes, which
supports an underlying difference in the establishment of the tumors. Understanding the functional role of each
mutation is necessary to design new therapeutics in pursuit of personalized medicine. Here, I propose to study
the role of the two major fibroid mutations, by over-expression of HMGA2 or by induction of a MED12 point
mutation in human primary myometrial cells. My central hypothesis is that over-expression of HMGA2 or MED12
mutation is each sufficient to induce a fibroid phenotype and that exploiting their transcriptome differences will
allow us to identify effective therapies specific to each subtype. In this application, I propose to 1) Determine the
functional roles of HMGA2 over-expression and MED12 mutation in uterine fibroids 2) Predict and test drug
compounds to target each of the two major fibroid subtypes using a spheroid model 3) Design in vitro assays
and test compounds by high throughput screening.
Career Goals: My Ph.D. is in pharmacology and toxicology, and I discovered that metallic nanoparticle exposure
during pregnancy can cross the placental barrier and impair normal fetal development. I became more interested
in women’s reproductive health during my postdoctoral training in Dr. Teixeira’s laboratory and made some
seminal discoveries. I found differential gene expression in the myometria of patients with fibroids compared to
those without fibroids and discovered transcriptomic differences in the myometria of Black and White women
that could be related to the racial disparity of these disease. I have also identified a novel myometrium stem cell
marker. My goal is to secure a tenure-track faculty position within an Academic Medical Center and develop in
vitro and in vivo models to test drugs for personalized therapeutics.
Career Development and Environment: The K99/R00 award will provide me the necessary training in drug
discovery using omics-data and high throughput screening to become a successful independent investigator. My
mentors will be Drs. Jose Teixeira, Bin Chen and Richard Neubig. Dr. Darlene Taylor is a specialist in the design
and s...

## Key facts

- **NIH application ID:** 10886903
- **Project number:** 1K99HD112539-01A1
- **Recipient organization:** HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Emmanuel Paul
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $107,860
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886903

## Citation

> US National Institutes of Health, RePORTER application 10886903, Understanding the functional role of fibroid subtype mutations for drug discovery (1K99HD112539-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10886903. Licensed CC0.

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