虹膜及睫状体上皮细胞在非感染性前葡萄膜炎发病中的作用

Non-infectious uveitis may account for as many as half of the clinical uveitis cases. It is generally agreed that the the disease is due to either autoimmune dysfunction or autoinflammmatory dysregulation in the eye. While much is known about the effector cells of the autoimmune and autoinflammatory responses, the early events which lead to the onset of inflammation remain largely undefined. We hypothesize that inflammation-prone changes of the intraocular milieu render the host eye “inflammation-susceptible”, which is a sub-inflammatory state precede the onset of clinical non-infectious uveitis. We also believe that iris and ciliary epithelial cells are the main contributors to such pro-inflammatory changes in the anterior segment of the eye. To test this hypothesis, we propose to first delineate molecular and cellular changes in cultured iris and ciliary body epithelial cells upon various stimuli, find out mechanisms which control the balance between “anti-inflammatory” and “pro-inflammatory” status of the cell. Based on these results, we aim to develop “inflammation-susceptible” mouse models, which should have the important feature of developing overt inflammation upon slight insult which is otherwise non-effective to healthy controls. We would further test the role of iris and ciliary epithelial cell-expressed p38MAP kinase in the development of the “inflammation-susceptible” status using cell/tissue specific p38α gene knockout mice. Finally, we would use the animal model to test the possibility and conditions associated with CMV-induced uveitis. The research proposed here addresses a difficult yet critical issue in the development of uveitis: the role of environmental changes in the development of non-infectious uveitis. We believe the outcome of the project would greatly further our understanding in the pathogenesis of idiopathic uveitis.

非感染性葡萄膜炎的发病机理始终是眼免疫研究的热点和难点。根据已有实验证据，我们提出眼内“炎症易感性”假说，即眼内微环境的趋炎性变化使其对外界的炎症刺激变得敏感，在微环境没有改善的情况下，炎症反应容易复发并可能加重。我们认为导致眼内“炎症易感性”的主要原因是眼内结构性细胞的炎性反应，其中虹膜和睫状体上皮细胞在抑制免疫反应和分泌炎症因子之间的平衡是决定前房免疫微环境的主要推手。为验证上述理论，我们计划首先在虹睫上皮细胞中寻找导致其产生炎症反应的刺激因素和机制，在此基础上建立炎症易感型小鼠模型，结合特异性基因敲除小鼠重点剖析上述细胞中p38MAP激酶在介导眼内炎症易感中的作用，最后运用上述动物模型探索目前葡萄膜炎学界颇有争议的关于巨细胞病毒在免疫正常人眼内局部活化导致葡萄膜炎的实验依据。本课题着眼于非免疫细胞对前房炎症发生的影响，将为非感染性葡萄膜炎发病机制提供崭新的线索和模型。

非感染性葡萄膜炎是葡萄膜炎临床的一个重要和棘手的问题，随着我们国家卫生和经济条件的大幅度提高，非感染性葡萄膜炎在我国葡萄膜炎患者中的比例也越来越高。葡萄膜炎作为眼内不正常免疫反应的统称，可以发生在从泪液、角膜到房水、视网膜和脉络膜的眼内各种组织和各种表现。本课题首先探索了青少年儿童人群中眼表非感染性过敏反应的发生率，发现其在上海市中小学生中发病高达28%，其中小学生人群中涉及影响日常生活的比例高达10.6%。进一步研究发现角膜基质细胞中Notch1基因在维持角膜稳态和组织修复中有重要作用，其基因缺失小鼠角膜上皮增生和角质化，并诱发严重的炎症反应。同时我们发现玉米黄素对角膜和结膜上皮细胞具有抗紫外损伤的作用。在眼内，房水是重要的液态细胞外基质，房水中炎症因子的变化是眼内炎症反应的风向标，我们的研究发现“正常”（即无其他眼部问题的单纯白内障眼）儿童和成人以及老年人群中房水中细胞因子和生长因子有显著差别，此项研究的意义在于为不同年龄段房水中上述因子的提供了基准指标。在眼底组织中，我们发现血小板反应蛋白1（TSP1）可以在体外培养的脉络膜血管细胞中减轻氧化应激带来的各项损伤，而其作用机制在于通过SHP-2调控STAT3-iNOS信号通路，减轻氧化压力对细胞的损伤，我们同时在小鼠体内发现TSP1能减少小鼠视网膜氧化压力以及脉络膜新生血管的产生。这部分研究结果对于湿性黄斑变性发生的预防和治疗都有潜在的意义。与此同时我们结合临床需要，对常发于幼儿的眼弓蛔虫病的在眼内的炎症反应进行了系统研究，提出用房水中特异性抗体及细胞因子检测辅助临床诊断。本项目的研究包含基础、临床及公共卫生相关内容，为进一步了解眼内炎症反应的特点提供了科学证据。

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