A transgenic model of ocular inflammation

眼部炎症的转基因模型

基本信息

批准号：
7171791
负责人：
Russell N. Van Gelder
金额：
$ 14.86万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-01 至 2007-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7171791
关键词：
Adverse effects Affect Animal Model Anterior uveitis Anti-Inflammatory Agents Anti-inflammatory Antibodies Autoimmune Process Azathioprine Basic Science Blindness Bos taurus Cataract Cattle Chlorambucil Choroiditis Chronic Disease Clinical Clinical Research Coxibs Cyclophosphamide Cyclosporine Diabetic Retinopathy Disease Engineering Etiology Eye Eye diseases Genes Genetic Glaucoma Human Immunization Incidence Individual Inflammation Inflammatory Injury Iritis Lac Repressors Legal Blindness Life Macular degeneration Mammalian Cell Methotrexate Modeling Modems Molecular Mimicry Mouse Strains Mus Numbers Pathogenesis Patients Peptides Personal Communication Persons Pharmaceutical Preparations Photoreceptors Pigments Preclinical Drug Evaluation Prevalence Proteins Rate Rattus Research Resources Retinitis Sequence Analysis Steroids Sympathetic Ophthalmia System Systemic disease T-Lymphocyte Tissues Transcription Coactivator Transgenic Mice Transgenic Model Transplanted tissue Tumor Necrosis Factor-alpha Tumor Necrosis Factors United States Ursidae Family Uveitis Vision Yeasts autoimmune uveitis human TNF protein immunogenic mouse model pathogen promoter

项目摘要

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.

描述（由申请人提供）：炎症性眼病是全世界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，对疾病发病机制的了解有限。目前还没有用于筛选具有抗葡萄膜炎活性的药物的生物学相关系统。现有的少数葡萄膜炎小鼠模型没有利用现代小鼠遗传学的新兴资源。我们建议通过生成多组转基因小鼠来创建葡萄膜疾病的新模型，这些转基因小鼠经过改造可在特定的眼组织亚群中表达特定的免疫原性蛋白（源自眼部病原体）。我们预测，当这些转基因小鼠受到这些病原体的攻击时，它们将会患上眼部炎症性疾病。也就是说，可以通过分子模拟生成合成葡萄膜炎模型。这项研究将优化用于哺乳动物细胞和转基因小鼠的酵母 Gal4-UAS 反式激活系统，并通过适应哺乳动物的 lac 阻遏系统添加变阻器功能；创建在眼组织特异性启动子控制下表达Gal4转录激活因子的转基因小鼠，以及在UAS上游识别序列控制下表达特定蛋白质的转基因小鼠；并分析这些小鼠品系后代的自发炎症以及病原体和病原体蛋白免疫后的炎症。