Novel regulatory role of cryopyrin in inflammation

描述（由申请人提供）：家族性感冒自身炎症综合征（FCAS）是一种常染色体显性遗传病，其特征是全身暴露于寒冷后反复发作皮疹、发烧和关节痛。这种疾病是由编码crypyrin的CIAS1基因突变引起的。Cryopyrin是新发现的NOD蛋白家族的一员，它们具有相似的结构域并参与炎症过程。虽然已知与crypyrin相关的疾病很少见，但NOD家族的另一个成员NOD2除了罕见的遗传性肉芽肿疾病Blau综合征外，还与常见的炎症性疾病克罗恩病有关。有证据表明，crypyrin在更常见的炎症性疾病（如类风湿关节炎）中也起作用。这个令人兴奋的概念使我们提出了一些研究，这些研究将阐明crypyrin在炎症，特别是关节炎中的作用，这可能对理解病理生理学和炎症疾病创新治疗的发展产生重大影响。

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.