Understanding the functional role of fibroid subtype mutations for drug discovery - 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 synthesis of drug delivery systems and will serve as a collaborator. The diverse departments at Michigan State University are ideal for me to complete the training to uncover novel specific and personalized therapies.
