Endometriosis is a chronic, estrogen-dependent gynecological disorder affecting 10-15% of reproductive age women which is characterized by the presence of endometrial tissue outside the uterus, predominantly in the pelvic peritoneum, and resulting in pelvic pain and infertility. The long-term goal of this research is discovery of molecular mechanisms governing the pathogenesis of endometriosis, particularly fibrosis, for development of non-invasive diagnostics and fertility-sparing treatments. Lesion etiology is difficult to study in women because of the significant delays of 8-11 years from the onset of disease to diagnosis and variations in disease progression. Over the past 25 years the Fazleabas lab has developed the baboon as an appropriate model to examine the establishment and progression of endometriotic lesions. FOXC1 was identified as a major upstream regulator of differentially expressed genes in lesions compared to matched endometrium from transcriptomic analyses. FOXC1 gain-of-function is associated with tissue remodeling and mechanisms of fibrosis, a hallmark of endometriotic lesions hypothesized to be crucial to the underlying pathogenesis of lesions. Thus, increased expression of FOXC1 may be an important contributor to the development of fibrosis in endometriotic lesions. We hypothesize that increased FOXC1, as a consequence of transcriptional and post-transcriptional regulation, alters the function of epithelial and stromal cells to promote fibrosis in the ectopic endometrium. We will determine the transcriptional and post-transcriptional mechanisms that regulate the increased expression of FOXC1 in endometriotic lesions (Aim 1), and the effects of FOXC1 expression on epithelial to mesenchymal (EMT) and fibroblast to myofibroblast (FMT) transitions, two components that contribute to fibrosis in endometriotic lesions. The proposed studies will provide key insight into the regulation and downstream effects of increased FOXC1 expression to uncover critical mechanisms in the pathogenesis of fibrosis in endometriotic lesions. The technical experience from these studies and career training from my sponsor and co-sponsors will prepare me for a successful independent research career for investigating endometriosis and disorders of the female reproductive tract to improve human health.
Endometriosis is a non-malignant disorder affecting 10-15% of reproductive-age women associated with debilitating chronic pelvic pain and impaired fertility. FOXC1 was identified as a central transcription factor through integrated transcriptomic analyses that may regulate epithelial-mesenchymal and fibroblast- myofibroblast transition pathways in endometriotic lesions. The proposed studies will have a significant impact on our understanding of the underlying mechanisms of pathology and fibrosis in endometriotic lesions and advance our efforts to identify early diagnostic markers and non-hormonal treatments of endometriosis.