Macrophage migration inhibitory factor and endometriosis

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DESCRIPTION (provided by applicant): Endometriosis is a chronic disease characterized by pelvic pain and infertility which affects over 70 million women world-wide. Despite its prevalence, the mechanisms which predispose women to the development of this disease remain largely unknown. Macrophage migration inhibitory factor (MIF) is elevated in the peritoneal fluid and serum of women with endometriosis as is its expression in both ectopic and eutopic endometrium. However, other than an associational relationship, it is uncertain if this cytokine plays an active role in the development and/or progression of the disease, what factors lead to its elevated expression and if MIF could be targeted as a potential therapeutic modality in the treatment of endometriosis. In the current application we demonstrate using a mouse model of endometriosis that endometriotic implant expression of MIF is elevated compared to eutopic uterine tissue and that MIF is steroidally regulated in eutopic endometrium. The specific hypothesis to be tested in the current application is that as endometriosis progresses, endometriotic implant levels of MIF are increased and this requires peritoneal-endometriotic tissue interactions. Further, we propose that anti-MIF therapy will reduce the biological function of MIF within the implant and in turn induce regression of the disease. To accomplish these objectives two Specific Aims are proposed. In Specific Aim I we will use two mouse models for endometriosis; one in which endometriosis is induced in the peritoneal cavity and the other in which the disease is established subcutaneously. This approach will allow us to demonstrate that the peritoneal environment functionally contributes to the elevated MIF production by endometriotic tissue. In Specific Aim II we will demonstrate using the peritoneal mouse model of endometriosis that MIF enhances endometriotic implant growth and that inhibition of MIF activity results in a regression of the disease. Collectively, these studies will demonstrate that MIF production increases as endometriosis develops in the peritoneal cavity, that MIF plays a functional role in the progression of the disease and that inhibiting MIF activity results in regression of the disease. PUBLIC HEALTH RELEVANCE: Endometriosis is a disease most common to women of reproductive age which results in pelvic pain and infertility. Macrophage migration inhibitory factor (MIF) is detected in elevated levels in women with endometriosis, but the potential role of this cytokine in the pathophysiology of the disease remains unclear. The proposed studies will begin to determine the mechanisms and mediators which lead to elevated MIF expression using a well-characterized animal model. Further the utility of anti-MIF therapy in suppressing the disease will be evaluated using this same animal model. The long-term benefits of this research will enhance our understanding on the disease endometriosis and more specifically the role of MIF in the pathophysiology of the disease. These studies may impact the development of treatment strategies that will improve the reproductive health of women. Relevance statement: Endometriosis is a significant disease in women of reproductive age. Understanding how the disease develops and identifying those factors which participate in the pathophysiology may allow for new treatments for this disease.