Macrophage migration inhibitory factor and endometriosis

巨噬细胞迁移抑制因子与子宫内膜异位症

• 批准号: 7871892
• 负责人: Warren B Nothnick
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871892
• 关键词: Affect; Age; Animal Model; Back; Biological Process; Capital; Chronic Disease; Development; Disease; Disease Progression; Disease regression; Dissection; Endometrium; Environment; Exhibits; Functional disorder; Future; Gene Proteins; Genes; Greater sac of peritoneum; Growth; Human; Implant; Infertility; Lead; Letters; Mediator of activation protein; Migration Inhibitory Factor; Modality; Modeling; Mus; Nomenclature; Pelvic Pain; Peritoneal; Peritoneal Fluid; Play; Prevalence; Production; Proteins; Reproductive Health; Research; Role; Series; Serum; System; Testing; Therapeutic; Tissues; Woman; cytokine; endometriosis; human disease; improved; inhibitor/antagonist; innovation; mouse model; novel; phenylpyruvate tautomerase; public health relevance; reproductive; research study; treatment strategy

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.

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为特征的慢性疾病，影响着全世界超过 7000 万女性。尽管这种疾病很普遍，但导致女性患上这种疾病的机制仍然很大程度上未知。子宫内膜异位症女性的腹腔液和血清中的巨噬细胞迁移抑制因子（MIF）在异位和在位子宫内膜中的表达均升高。然而，除了相关关系之外，尚不确定该细胞因子是否在疾病的发生和/或进展中发挥积极作用、哪些因素导致其表达升高以及 MIF 是否可以作为治疗中的潜在治疗方式子宫内膜异位症。 在当前的应用中，我们使用子宫内膜异位症小鼠模型证明，与在位子宫组织相比，MIF 的子宫内膜异位植入物表达升高，并且 MIF 在在位子宫内膜中受到类固醇调节。本申请中要测试的具体假设是，随着子宫内膜异位症的进展，MIF的子宫内膜异位植入水平增加，这需要腹膜-子宫内膜异位组织相互作用。此外，我们建议抗 MIF 治疗将降低植入物内 MIF 的生物学功能，进而诱导疾病消退。为了实现这些目标，提出了两个具体目标。在具体目标 I 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，另一种是在皮下引起子宫内膜异位症。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组织增加 MIF 的产生。在特定目标 II 中，我们将使用子宫内膜异位症的腹膜小鼠模型证明 MIF 增强子宫内膜异位植入物的生长，并且抑制 MIF 活性会导致疾病消退。总的来说，这些研究将证明，随着子宫内膜异位症的发展，MIF 的产生会增加。 腹膜腔中，MIF 在疾病的进展中发挥功能性作用，抑制 MIF 活性会导致疾病消退。 公共卫生相关性：子宫内膜异位症是育龄妇女最常见的疾病，会导致骨盆疼痛和不孕。在患有子宫内膜异位症的女性中检测到巨噬细胞迁移抑制因子（MIF）的水平升高，但这种细胞因子在该疾病的病理生理学中的潜在作用仍不清楚。拟议的研究将开始使用充分表征的动物模型来确定导致 MIF 表达升高的机制和介质。此外，将使用相同的动物模型来评估抗 MIF 疗法在抑制疾病方面的效用。这项研究的长期好处将增强我们对子宫内膜异位症的了解，更具体地说，是 MIF 在该疾病病理生理学中的作用。这些研究可能会影响改善妇女生殖健康的治疗策略的制定。相关性声明：子宫内膜异位症是育龄妇女的一种重要疾病。了解疾病如何发展并确定参与病理生理学的因素可能会为这种疾病提供新的治疗方法。