A Genetic Model of Uveitis

DESCRIPTION (provided by applicant): Uveitis research is poised to benefit from the discipline of genetics. Recently, mutations in a gene known as NOD2 (or CARD15) have been found to cause Blau syndrome (also called Jabs disease or familial juvenile systemic granulomatosis), a rare form of uveal, skin and joint granulomatous inflammation. Blau syndrome is inherited in an autosomal dominant pattern, and the discovery that a single amino acid change in the NOD2 protein can result in uveitis provides an incredible research opportunity. The NOD2 gene product can participate in inflammatory responses by activating NFkappaB in response to the bacterial peptidoglycan subunit, muramyl dipeptide. NOD2 also contains a protein domain that may allow participation in apoptotic cellular pathways. The exact mechanisms by which NOD2 may be involved in initiating, prolonging or regulating immune responses relating to ocular inflammation is unknown. In an effort to produce a genetic model of uveitis, and to study the basic biology of NOD2 as it relates to ocular inflammatory responses, this is a proposal to create transgenic mice expressing the wild-type NOD2 cDNA and expressing a representative Blau syndrome NOD2 mutation. The specific aims are as follows: 1. To determine the expression pattern of NOD2 in the normal mouse. This will be accomplished by creating a mouse expressing a bicistronic murine NOD2 and yellow fluorescent protein transgene. Expression in several tissues will be examined, with particular attention paid to ocular tissues. Both normal and inflamed eyes will be studied. 2. To examine whether over-expression of NOD2 alters susceptibility to muramyl dipeptide-induced uveitis. Since NOD2 appears to regulate the intracellular response to muramyl dipeptide and because muramyl dipeptide is a known trigger of uveitis, the hypothesis that over-expression of NOD2 increases intensity of uveitis in a murine model will be tested. 3. To test the hypothesis that expression of NOD2 with a Blau syndrome mutation results in a model of spontaneous uveitis. Both transgenic mice and transgenic mice crossed with NOD2 knock-out mice will be studied.