The Role of Cryopyrin in Autoinflammatory Diseases

描述(申请人提供)：炎症基本上是一种保护机制；然而，在过敏性、自身免疫性和自体炎症性疾病中，炎症过程的变化会导致疾病。炎症可由病原体和全身寒冷暴露等各种刺激引发，先天免疫系统在这些反应中发挥作用。虽然最近研究的重点很密集，但先天免疫系统的特性还不是很好。家族性冷自炎综合征(FCAS)是研究先天免疫和免疫系统对物理刺激反应的良好模型。对FCAS分子机制的研究已经导致了针对这种疾病的新的有效的细胞因子靶向治疗。在FCAS中发现的突变基因(CIAS1)和蛋白质(低温比林)可能在更常见的炎症性疾病中发挥重要作用，如类风湿性关节炎和痛风。我们对CIAS1和低温比林的发现引起了人们对一类新的细胞内天然免疫受体家族的关注，这些受体被称为核苷酸结合域-亮氨酸丰富重复序列(NLRs)，它们与Toll样受体具有共同的特征，而Toll样受体是天然免疫反应中不可或缺的一部分。低温比林在先天免疫中的作用正在研究中，低温比林已被证明可以感知各种外源性和内源性危险信号。低温比林广泛的选择性剪接可能是天然免疫系统中为多个配体创造特异性的一种机制。这项提议的主要目标是描绘低温比林在寒冷反应中介导炎症的过程，并确定这一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，特别是当它与配体特异性和蛋白质功能有关时。将开展下列实验：1)利用人和小鼠模型进行体外和体内研究，以确定寒冷介导炎症反应的分子机制；2)系统研究宿主与病原体的反应，以确定FCAS相关的低温比蛋白突变对体外小鼠和人类单核/巨噬细胞反应的影响，以及对系统性体内小鼠反应的影响；3)研究低温比蛋白亚型的表达模式、功能和配体特异性。了解自体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)它将允许开发针对目前几乎没有有效治疗方法的炎症性疾病的新的靶向疗法；2)它可能为提高对感染的抵抗力提供见解；3)了解物理刺激(如寒冷)如何引发炎症可能导致针对寒冷诱导的疾病的保护疗法。

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.