Molecular mechanisms underlying endometriosis-associated infertility

Project Summary/Abstract Endometriosis affects 10-15% of women of reproductive age, and the incidence increases to 50-60% in women with severe pelvic pain and infertility. Unfortunately, current diagnostic and therapeutic strategies have major limitations, leading to delays in diagnosis and adverse side effects to treatments. Therefore, our long-term research goal is to define critical pathophysiological and molecular mechanisms that regulate endometriosis development and related infertility and to translate those findings toward better diagnostic strategies and improved treatments. Recent clinical findings demonstrated that the transcription factor forkhead box A2 (FOXA2) is significantly decreased or entirely lost in the glandular epithelium of women and mice with endometriosis and is implicated in a variety of additional uterine pathologies including infertility. However, our understanding of FOXA2 biology and its role in endometriosis is very incomplete. Our recent studies revealed that stroma from women with endometriosis suppresses epithelial FOXA2 expression and that loss of FOXA2 increases endometriotic lesion establishment in the mouse. In this regard, we have evidence that FOXA2 regulates uterine expression of Leukemia inhibitory factor (LIF) and have found that administering LIF prevents the establishment and growth of endometriotic lesions in the mouse. The central hypotheses of this application are that (1) FOXA2 loss disrupts key developmental and cellular differentiation pathways, leading to decreased fertility and ectopic endometriotic lesion development, growth, and survival; and (2) FOXA2- regulated LIF provides a novel therapeutic target for endometriosis and its related infertility. A team of exceptional investigators with complementary and substantial expertise in reproductive biology, innovative in vivo and in vitro models, nanoparticle development, and bioinformatics will address that hypothesis by conducting a collaborative research project. Guided by strong published and preliminary data, two specific aims are proposed: (1) Dissect the role of FOXA2 in the development and progression of endometriosis-related infertility; and (2) Evaluate the theranostic potential of LIF-loaded nanoparticles treatment for endometriosis. The proposed approach couples the use of mouse genetic models with that of human 3D culture models to provide translatable genetic and mechanistic information relevant to endometriosis biology. In addition, human and mouse models will be leveraged to evaluate the therapeutic potential of LIF-loaded nanoparticle treatment for endometriosis and its related infertility. The proposed studies are conceptually and technically innovative and together will have a broad impact on the field by filling a substantial gap in our fundamental knowledge of endometriosis pathobiology. In the long term, an increased understanding of the cellular and molecular mechanisms that govern endometrial epithelial cell function is important not only for gaining fundamental knowledge of endometriosis pathobiology but also for the development of therapeutics for the treatment of additional uterine pathologies.