Endometriosis is a chronic disease in which endometrial tissue grows ectopically, is characterized by pelvic pain and infertility and affects over 70 million women world-wide. One of the reasons for its high prevalence is that the disease is usually diagnosed only after it has established. An additional clinical shortcoming is that the majority of treatments for the disease rely on the induction of a hypoestrogenic state which is associated with unwanted side effects and negative impacts on bone health. Clearly, both better diagnostic tools and treatment options are warranted. microRNAs have emerged as critical post-transcriptional regulators of gene expression that are fundamental for development and function of many organ systems. Recent reports have suggested that miRNAs are mis-expressed in endometriosis. While these reports have laid the initial groundwork to examine the potential role of miRNAs in the pathophysiology of the disease, they have provided no functional evidence demonstrating a role for miRNAs in the development of endometriosis. To fill this gap in our knowledge, the current application will test the overall hypothesis that miR-451 expression is significantly reduced in women with endometriosis and this reduction in turn leads to endometriotic implant growth via increases in cell proliferation and invasion. We further propose, based upon this mis-expression, that miR-451 may prove useful as a diagnostic marker and/or a therapeutic target for endometriosis. To test this hypothesis, we will: 1) demonstrate that miR-451 functionally dictates growth of endometriotic implants and that miRNA restoration therapy is an effective, non-steroidal approach to treating the disease, 2) dissect the molecular mechanisms by which miR-451 regulates key targets which are essential for endometriotic implant growth and 3) assess miR- 451 serum levels in women as well as baboons with and without endometriosis to determine if there is a correlation between presence of disease and levels of miR-451. As such, this application will provide new knowledge in the rapidly expanding field of miRNAs and provide the first assessment of a functional role of miRNAs in the pathophysiology of endometriosis. Further, these studies will conduct the initial studies to evaluate the utility of miR-451 as a diagnostic marker for the disease as well as provide insight into the possible application of novel, miRNA-based therapies for endometriosis treatment. The long-term benefits of this research will enhance our understanding on the disease endometriosis and has the potential to improve women's health. The outcomes from the proposed research have the potential to change the way endometriosis may be treated and/or diagnosed.

Public Health Relevance

Endometriosis is a significant disease in women of reproductive age. Understanding how the disease develops and identifying those factors which participate in the pathogenesis may allow for new treatments and diagnostic tools for this disease.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Parrott, Estella C
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University of Kansas
Obstetrics & Gynecology
Schools of Medicine
Kansas City
United States
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Nothnick, Warren B (2017) MicroRNAs and Endometriosis: Distinguishing Drivers from Passengers in Disease Pathogenesis. Semin Reprod Med 35:173-180
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
Nothnick, Warren B (2016) Non-coding RNAs in Uterine Development, Function and Disease. Adv Exp Med Biol 886:171-189
Nothnick, Warren B; Al-Hendy, Ayman; Lue, John R (2015) Circulating Micro-RNAs as Diagnostic Biomarkers for Endometriosis: Privation and Promise. J Minim Invasive Gynecol 22:719-26
Rao, Deepthi; Kimler, Bruce F; Nothnick, Warren B et al. (2015) Transgelin: a potentially useful diagnostic marker differentially expressed in triple-negative and non-triple-negative breast cancers. Hum Pathol 46:876-83
Graham, Amanda; Falcone, Tommaso; Nothnick, Warren B (2015) The expression of microRNA-451 in human endometriotic lesions is inversely related to that of macrophage migration inhibitory factor (MIF) and regulates MIF expression and modulation of epithelial cell survival. Hum Reprod 30:642-52
Tawfik, Ossama; Rao, Deepthi; Nothnick, Warren B et al. (2014) Transgelin, a Novel Marker of Smooth Muscle Differentiation, Effectively Distinguishes Endometrial Stromal Tumors from Uterine Smooth Muscle Tumors. Int J Gynecol Obstet Reprod Med Res 1:26-31
Nothnick, Warren B; Graham, Amanda; Holbert, Joshua et al. (2014) miR-451 deficiency is associated with altered endometrial fibrinogen alpha chain expression and reduced endometriotic implant establishment in an experimental mouse model. PLoS One 9:e100336