REST/NRSF, miRNAs, and tissue remodeling in adenomyosis pathophysiology

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Project Summary Adenomyosis is a nonmalignant uterine disease characterized by endometrial stroma and glands found within the myometrium. Adenomyosis has been associated with heavy and painful menstrual periods, pelvic pain, pain with intercourse, and reproductive dysfunction. However, now that imaging is identifying adenomyosis in younger and more varied women than those electing hysterectomy where pathological diagnosis occurred, many of our assumptions about the clinical disease are changing. Additionally, the only widely accepted and effective treatments for adenomyosis, hysterectomy and hormonal suppression, are unacceptable for this wider group of women. Much of our uncertainty on diagnosis and treatment for adenomyosis stem from our uncertainty on its' pathogenesis. The most common theory of adenomyosis development centers on the involvement of tissue injury and repair mechanisms with resulting adenomyosis development from invagination of the endometrial basalis into the myometrium (the invasion/invagination theory). While emerging data support a role for this theory and the involvement of cell migration, proliferation and invasion in adenomyosis development, a detailed understanding on the mediators and mechanisms is clearly lacking. To fill this critical gap in our knowledge we will perform a series of experiments which integrate well-defined human specimens, novel mouse models and rigorous in vitro approaches to identify key components of a REST-miRNA-tissue remodeling cascade and demonstrate the functionality of this pathway in the pathogenesis of adenomyosis. The specific hypothesis to be tested in this application is that reduced expression of endometrial and/or myometrial REST induces alterations in a miRNA-mediated tissue remodeling cascade which augments adenomyosis development. To test this hypothesis, we will delineate expression of a novel REST-miRNA mediated tissue remodeling pathway in adenomyosis and define REST's function using novel experimental mouse models. Using in vitro models for cell proliferation, migration and invasion, we will decipher cell to cell communication between myometrial-endometrial REST-miRNA tissue remodeling pathway signaling relevant to adenomyosis pathophysiology. Together, these experiments will provide novel insight into the role of REST in adenomyosis development and in turn, may lead to identification of novel treatment targets for this disease.