Novel regulatory role of cryopyrin in inflammation

描述(申请人提供)：家族性感冒自体炎症综合征(FCAS)是一种常染色体显性遗传性疾病，特征是广泛暴露在寒冷中后反复发作皮疹、发烧和关节痛。这种疾病是由编码低温比林的CIAS1基因突变引起的。低温比林是新近发现的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。尽管已知的与低温比林相关的疾病很少见，但NOD家族的另一成员NOD2除了罕见的遗传性肉芽肿疾病布劳综合征外，还与常见的炎症性疾病克罗恩病有关。有证据表明，低温比林也在更常见的炎症性疾病中发挥作用，如类风湿性关节炎。这一令人兴奋的概念使我们提出了一些研究，这些研究将阐明低温比林在炎症中的作用，特别是在关节炎中的作用，这可能对理解炎症疾病的病理生理学和开发创新的治疗方法产生重大影响。 在研究低温比林在人类中的表达和功能方面已经取得了重大进展。虽然从对受影响的人类受试者的研究中可以学到很多东西，而且可以使用体外系统对一些机制进行建模，但在小鼠身上进行建模提供了在整个动物的背景下研究基因功能的最大潜力。小鼠和人类Cas在结构和表达上的相似性使小鼠很有可能成为研究人类炎症反应和疾病的优秀模型。这项研究计划的目标是利用新的噬菌体展示技术生产单抗，以及其他现有的小鼠建模和试剂生产方法，来探索低温比林在急性和慢性炎症中的作用。

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.