A transgenic model of ocular inflammation

描述（由申请人提供）：炎症性眼病是世界范围内视力下降和失明的主要原因。葡萄膜炎的动物模型相对较少，对其发病机制的认识有限。目前还没有生物学上相关的筛选抗葡萄膜炎药物的系统。现有的几种葡萄膜炎小鼠模型没有充分利用新兴的现代小鼠遗传学资源。我们建议通过产生转基因小鼠，在特定的眼组织亚群中表达特异性免疫原性蛋白（来自眼部病原体），来创建一种新的葡萄膜病模型。我们预测这些转基因小鼠在受到这些病原体的攻击时会发生眼部炎症；也就是说，通过分子模拟可以生成合成的葡萄膜炎模型。本研究将优化酵母Gal4-UAS反激活系统，用于哺乳动物细胞和转基因小鼠，并与哺乳动物适应的lac-阻遏系统一起增加变阻器功能；建立在眼组织特异性启动子控制下表达Gal4转录激活子的转基因小鼠，以及在UAS上游识别序列控制下表达特异性蛋白的转基因小鼠；并分析这些小鼠后代的自发性炎症以及病原体和病原体蛋白免疫后的炎症。

DESCRIPTION (provided by applicant): Inflammatory eye disease is a major cause of decreased vision and blindness worldwide. Relatively few animal models of uveitis exist, which has limited understanding of disease pathogenesis. No biologically relevant system for screening of drugs active against uveitis is available. The few existing mouse models of uveitis do not take advantage of the burgeoning set of resources of modem mouse genetics. We propose creating a new model for uveitic disease by generating sets of transgenic mice engineered to express specific immunogenic proteins (derived from ocular pathogens) in specific subsets of ocular tissue. We predict that such transgenic mice will develop ocular inflammatory disease when challenged with those pathogens; that is, a synthetic uveitis model can be generated by molecular mimicry. This research will optimize the yeast Gal4-UAS transactivating system for use in mammalian cells and in transgenic mice, and add rheostat function with the mammalian-adapted lac-repressor system; create transgenic mice expressing the Gal4 transcriptional activator under the control of ocular tissue-specific promoters, and transgenic mice expressing specific proteins under the control of the UAS upstream recognition sequence; and analyze offspring of these mouse strains for spontaneous inflammation as well as inflammation following immunization with pathogen and pathogen protein.