Novel regulatory role of cryopyrin in inflammation

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DESCRIPTION (provided by applicant): Familial cold autoinflammatory syndome (FCAS) is an autosomal dominant disorder characterized by recurrent episodes of rash, fever, and arthralgia following generalized exposure to cold. This disease is caused by mutations in the CIAS1 gene, which codes for cryopyrin. Cryopyrin is a member of the newly identified family of NOD proteins, which share similar structural domains and involvement in inflammatory processes. Although the known diseases associated with cryopyrin are rare, another member of the NOD family, NOD2, has been associated with the common inflammatory disorder, Crohn's disease, in addition to the rare inherited granulomatous disease, Blau Syndrome. There is evidence that cryopyrin also plays a role in more common inflammatory diseases such as rheumatoid arthritis. This exciting concept has led us to proposed studies that will elucidate the role of cryopyrin in inflammation, specifically in arthritis, which could have a major impact on understanding the pathophysiology and the development of innovative treatments for inflammatory disorders. There has been significant progress in characterizing the expression and function of cryopyrin in humans. While a great deal can be learned from studies of affected human subjects, and some mechanisms can be modeled using in vitro systems, modeling in the mouse provides the greatest potential to study gene function in the context of the whole animal. The similarities in structure and expression of mouse and human CIAS1make it very likely that the mouse will provide an excellent model for human inflammatory responses and diseases. The goal of this research proposal is to explore the function of cryopyrin in acute and chronic inflammation using novel phage display techniques for monoclonal antibody production, in addition to other existing methodologies for mouse modeling and reagent production.