The Role of Cryopyrin in Autoinflammatory Diseases

描述（由申请人提供）：炎症基本上是一种保护机制;然而，在过敏性、自身免疫性和自身炎症性疾病中，炎症过程的改变导致疾病。炎症可以由病原体和全身性寒冷暴露等各种刺激引发，先天免疫系统在这些反应中起作用。虽然最近的重点是密集的研究，先天免疫系统没有得到很好的表征。家族性寒冷自身炎症综合征（FCAS）是研究先天免疫和免疫系统对物理刺激反应的极好模型。对FCAS分子机制的研究已经导致了针对该疾病的新型有效的细胞因子靶向疗法。在FCAS中发现的突变基因（CIAS 1）和蛋白质（cryopyrin）可能在更常见的炎症性疾病（如类风湿性关节炎和痛风）中发挥重要作用。我们对CIAS 1和cryopyrin的鉴定引起了人们对一个新的细胞内先天免疫受体家族的关注，该家族被称为核苷酸结合结构域-富含亮氨酸的重复序列（NLR），其与Toll样受体具有共同的特征，Toll样受体是先天免疫应答中不可或缺的。Cryopyrin在先天免疫中的作用正在研究中，cryopyrin已被证明可以感知各种外源性和内源性危险信号。Cryopyrin广泛的选择性剪接可能是先天免疫系统中产生对多种配体的特异性的一种机制。该提案的主要目标是描述cryopyrin介导炎症反应的过程，并确定该过程是否对病原体具有保护作用。这将需要确定选择性剪接的作用，特别是因为它涉及配体特异性和蛋白质功能。将进行以下实验路线：1）将利用人和小鼠模型的体外和体内研究来鉴定冷介导炎症反应的分子机制; 2）将进行宿主-病原体应答的系统性研究以确定FCAS相关的cryopyrin突变对体外小鼠和人单核细胞/巨噬细胞的影响。巨噬细胞反应和全身性体内小鼠反应; 3）将研究冷比林同种型的表达模式、功能性和配体特异性。了解自身炎症和先天免疫反应的机制将对人类健康产生影响，原因有几个：1）它将允许开发新的靶向治疗炎症疾病的方法，目前这些疾病的有效治疗方法很少; 2）它可以提供对提高抗感染能力的方法的见解; 3）了解物理刺激（如寒冷）如何引发炎症，可能会导致预防寒冷引起的疾病的治疗。

DESCRIPTION (provided by applicant): Inflammation is fundamentally a protective mechanism; however, in allergic, autoimmune, and autoinflammatory disorders, alterations in the inflammatory processes result in disease. Inflammation can be initiated by such varied stimuli as pathogens and generalized cold exposure, and the innate immune system plays a role in these responses. Although recently the focus of intense study, the innate immune system is not well characterized. Familial cold autoinflammatory syndrome (FCAS) is an excellent model for the study of innate immunity and the immune system's response to physical stimuli. Study of the molecular mechanisms of FCAS has led to novel effective cytokine targeted therapies for the disorder. The mutated gene (CIAS1) and protein (cryopyrin) identified in FCAS may play an important role in more common inflammatory disorders such as rheumatoid arthritis and gout. Our identification of CIAS1 and cryopyrin has brought attention to a new family of intracellular innate immune receptors known as Nucleotide binding domain-Leucine rich Repeats (NLRs) that share common features with Toll-like receptors which are integral in innate immune response. Cryopyrin's role in innate immunity is under study, and cryopyrin has been shown to sense a variety of exogenous and endogenous danger signals. Cryopyrin's extensive alternative splicing may be one mechanism in the innate immune system for creating specificity for multiple ligands. The main goal of this proposal is to delineate the processes through which cryopyrin mediates inflammation in response to cold and determine if this process is protective against pathogens. This will necessitate identification of the role of alternative splicing, especially as it relates to ligand specificity and protein function. The following lines of experimentation will be carried out: 1) In vitro and in vivo studies with both human and mouse models will be utilized to identify the molecular mechanisms through which cold mediates inflammatory responses; 2) Systematic studies of the host-pathogen response will be performed to determine the effects of FCAS-associated cryopyrin mutations on in vitro mouse and human monocyte/macrophage response and systemic in vivo mouse response; 3) Expression patterns, functionality, and ligand specificity of cryopyrin isoforms will be studied. Understanding the mechanisms of auto-inflammatory and innate immune responses will impact on human health for several reasons: 1) It will allow for the development of new targeted therapies for inflammatory conditions which currently have few effective treatments; 2) It may provide insights into a means to improve resistance to infection; 3) Understanding how a physical stimulus such as cold can trigger inflammation may lead to therapies that are protective against cold induced disorders.