Novel regulatory role of cryopyrin in inflammation

描述（由申请人提供）：家族性寒冷自身炎性综合征（FCAS）是一种常染色体显性遗传疾病，其特征是全身暴露于寒冷后反复发作皮疹、发热和关节痛。这种疾病是由CIAS1基因突变引起的，CIAS1基因编码cryopyrin。Cryopyrin是新发现的NOD蛋白家族的成员，其具有相似的结构域并参与炎症过程。尽管已知的与冷比林相关的疾病是罕见的，但NOD家族的另一个成员NOD 2除了与罕见的遗传性肉芽肿性疾病Blau综合征相关之外，还与常见的炎性疾病克罗恩病相关。有证据表明，cryopyrin也在更常见的炎症性疾病如类风湿性关节炎中发挥作用。这一令人兴奋的概念使我们提出了一些研究，这些研究将阐明cryopyrin在炎症中的作用，特别是在关节炎中，这可能对理解炎症性疾病的病理生理学和创新治疗方法的发展产生重大影响。 在表征cryopyrin在人类中的表达和功能方面已经取得了重大进展。虽然可以从受影响的人类受试者的研究中学到很多东西，并且可以使用体外系统对一些机制进行建模，但在小鼠中建模提供了在整个动物背景下研究基因功能的最大潜力。小鼠和人CIAS 1在结构和表达方面的相似性使得小鼠很可能为人类炎症反应和疾病提供极好的模型。本研究计划的目标是探索cryopyrin在急性和慢性炎症中的功能，使用新的噬菌体展示技术生产单克隆抗体，以及其他现有的小鼠建模和试剂生产方法。

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.