Macrophage migration inhibitory factor and endometriosis

描述（由申请人提供）：子宫内膜异位症是一种以盆腔疼痛和不孕症为特征的慢性疾病，影响全球超过7000万妇女。尽管它很流行，但使妇女易患这种疾病的机制在很大程度上仍然未知。巨噬细胞迁移抑制因子（MIF）在子宫内膜异位症妇女的腹膜液和血清中升高，其在异位和异位子宫内膜中的表达也升高。然而，除了相关关系外，目前尚不清楚这种细胞因子是否在疾病的发生和/或进展中起积极作用，哪些因素导致其表达升高，以及MIF是否可以作为治疗子宫内膜异位症的潜在治疗方式。在目前的应用中，我们使用子宫内膜异位症小鼠模型证明，与异位子宫组织相比，子宫内膜异位症植入物的MIF表达升高，并且MIF在异位子宫内膜中受到类固醇调节。在当前应用中需要验证的具体假设是，随着子宫内膜异位症的进展，子宫内膜异位症植入物的MIF水平升高，这需要腹膜-子宫内膜异位症组织相互作用。此外，我们提出抗MIF治疗将降低MIF在植入物内的生物学功能，进而诱导疾病的消退。为实现这些目标，提出了两个具体目标。在特异性目的1中，我们将使用两种子宫内膜异位症小鼠模型；一种是在腹腔内诱发子宫内膜异位症，另一种是在皮下建立疾病。这种方法将使我们能够证明腹膜环境在功能上有助于子宫内膜异位症组织产生的MIF升高。在Specific Aim II中，我们将使用子宫内膜异位症的腹膜小鼠模型证明MIF促进子宫内膜异位症植入物的生长，抑制MIF活性导致疾病的消退。总的来说，这些研究将证明MIF的产生随着子宫内膜异位症的发展而增加

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.