This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.
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