Endometriosis, the presence of endometrial glands and stroma outside of the uterine cavity causes chronic pelvic pain and infertility. It affects 10% of women of reproductive age and 35-50% who are infertile. The average for clinical diagnosis takes 8-11 years and the molecular mechanisms associated with the pathophysiology still remains poorly understood. Our laboratory has undertaken pioneering research in the past 12 years during which we have characterized the causative factors and molecular changes that are involved in the early onset of the disease in a baboon model of experimentally induced endometriosis. MicroRNAs (miR), small non-coding RNAs which regulate posttranscriptional gene regulation, have emerged as important regulators that may contribute to pathophysiology of endometriosis. Our preliminary data suggests that induction of endometriosis leads to rapid and significant changes in the expression of several miRs. This application focuses specifically on the biological functions of miR-451 that is highly down regulated following induction of endometriosis. Changes in miR expression were reflected in the corresponding alterations of its target gene, YWHAZ. We hypothesize that these changes contribute to the progression of endometriosis and altered endometrial function. To test this hypothesis in Specific Aim 1 we propose to the determine mechanisms by which YWHAZ forms a complex with beta-catenin to promote cell proliferation and migration and inhibut apoptosis.
In Specific Aim 2 we will focus on xenograft experiments in immunocompromised mice and the targeted delivery of miR mimics, inhibitors and siRNA in vivo to test the efficacy of using miR-based therapeutic approaches for endometriosis. These innovative studies will contribute to our understanding of the molecular mechanisms underlying the etiology of endometriosis and functionally link miR expression to target genes that are pathologically relevant.
Endometriosis remains an enigmatic disease whose basic biology still eludes us. Based on our extensive studies in both the baboon and women, we are proposing innovative studies which are focused on how microRNA's contribute to the development of endometriosis and their potential use as therapeutic targets to inhibit the development of lesions.
| Nothnick, Warren B; Falcone, Tommaso; Joshi, Niraj et al. (2017) Serum miR-451a Levels Are Significantly Elevated in Women With Endometriosis and Recapitulated in Baboons ( Papio anubis) With Experimentally-Induced Disease. Reprod Sci 24:1195-1202 |
