Retinoid effects on inflammation and cell growth associated with endometriosis

描述(由申请者提供)：本项目的总体目标是了解维甲酸在子宫内膜异位症中的作用机制和临床潜力。我们认为，维甲酸在子宫内膜异位症的发生发展中起着致病作用，并具有治疗的潜力。为了支持这些假说，我们以前的工作已经证明，维甲酸对某些子宫内膜和免疫细胞功能有深远的影响，这些功能在子宫内膜异位症中是异常的，被认为与其发病和/或进展有关。尤其重要的是，我们提供的证据表明，维甲酸可以改变子宫内膜细胞和巨噬细胞的活性，预期对子宫内膜异位症患者有利。我们的总目标将通过四个具体目标来实现。目的1将评估在子宫内膜异位症中类维甲酸水平是否改变。这个问题将通过对子宫内膜组织、腹膜免疫细胞和腹膜细胞所处的腹膜环境中维甲酸的储存和代谢的详细分析来解决。目的2将确定与子宫内膜异位症患者的腹膜巨噬细胞有关的CD36上的维甲酸作用的生理学意义。这种B型清道夫受体在吸收和清除因月经逆行而植入腹膜的凋亡细胞和细胞碎片方面起着主要作用。我们已经证明，子宫内膜异位症患者的腹膜巨噬细胞中这种受体减少，维甲酸(RA)可以上调其表达。我们现在将确定CD36在子宫内膜异位症巨噬细胞中异常调节的性质，以及RA是否可以用于使该受体的表达和功能正常化。通过我们的研究表明，维甲酸还可以改变参与子宫内膜缝隙连接通讯的某些连接蛋白(CXS)的表达，AIM 3将验证我们的假设，即CXS通过参与子宫内膜细胞的生长、凋亡和侵袭潜能，在子宫内膜异位症中发挥重要作用。这些研究将建立子宫内膜异位症病变中CX异常表达与疾病发生发展的因果关系，并确定维甲酸类化合物对子宫内膜细胞中CXS的调节能力。最后，目标4将评估维甲酸在免疫活性小鼠模型中对子宫内膜异位症发展的影响。使用模拟大规模逆行月经的方法，该模型还将阐明免疫调节与子宫内膜细胞异位生长之间的关系。 项目简介：子宫内膜异位症是一个主要的公共卫生问题。由于目前的药物治疗有局限性，迫切需要更有效的治疗方案。从我们的研究中获得的信息将为使用维甲酸类化合物来阻止子宫内膜异位症病变的发生和生长提供基本的框架。

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the mechanism of action and clinical potential of retinoids in endometriosis. We propose that retinoids play both a causative role in the development of endometriosis and have therapeutic potential for its treatment. In support of these hypotheses, our previous work has demonstrated that retinoids have profound effects on certain endometrial and immune cell functions that are abnormal in endometriosis, and thought to be related to its pathogenesis and/or progression. Of particular importance, we provide evidence that retinoids can alter endometrial cell and macrophage activity in ways that would be expected to be beneficial to endometriosis subjects. Our overall goal will be accomplished by four specific aims. Aim 1 will assess whether retinoid levels are altered in endometriosis. This question will be addressed by detailed analyses of retinoid storage and metabolism in endometrial tissue, peritoneal immune cells, and the peritoneal milieu in which the cells reside. Aim 2 will determine the physiologic implications of retinoid action on CD36 as relates to peritoneal macrophages from women with endometriosis. This type-B scavenger receptor plays a primary role in the uptake and clearance of apoptotic cells and cell debris which seed the peritoneum as a result of retrograde menstruation. We have shown that this receptor is reduced in peritoneal macrophages from women with endometriosis and that retinoic acid (RA) can upregulate its expression. We will now determine the nature of the aberrant regulation of CD36 in endometriosis macrophages and whether RA can be used to normalize the expression and function of this receptor. Through our demonstration that retinoids can also alter the expression of certain connexins (Cxs) involved in endometrial gap junction communication, Aim 3 will test our hypothesis that Cxs play fundamental roles in endometriosis through their involvement in endometrial cell growth, apoptosis, and invasive potential. These studies will establish the cause and effect relationship between aberrant Cx expression in endometriotic lesions and the etiology/progression of this disease, and determine the ability to regulate Cxs in endometrial cells by retinoid compounds. Finally, Aim 4 will evaluate the effects of retinoids on the development of endometriosis in an immunocompetent mouse model. Using methodology that simulates a massive retrograde menses, this model will also shed light on the relationship between immune modulation and ectopic growth of endometrial cells. Project Narrative: Endometriosis is a major public health issue. Since current medical therapy has limitations, more effective treatment options are desperately needed. The information gained from our studies will provide the basic framework for the therapeutic use of retinoid compounds to impede the genesis and growth of endometriotic lesions.