The Role of Cryopyrin in Autoinflammatory Diseases

描述（由申请人提供）：炎症本质上是一种保护机制；然而，在过敏、自身免疫和自身炎症疾病中，炎症过程的改变导致疾病。炎症可以由多种刺激引起，如病原体和普遍的寒冷暴露，先天免疫系统在这些反应中起作用。先天免疫系统虽是近年来研究的热点，但对其特性的描述却并不充分。家族性感冒自体炎症综合征（FCAS）是研究先天免疫和免疫系统对物理刺激反应的一个很好的模型。对FCAS分子机制的研究导致了新的有效的细胞因子靶向治疗该疾病。在FCAS中发现的突变基因（CIAS1）和蛋白（cryopyrin）可能在更常见的炎症性疾病（如类风湿关节炎和痛风）中发挥重要作用。我们对CIAS1和crypyrin的鉴定引起了人们对细胞内先天免疫受体新家族的关注，这些受体被称为核苷酸结合域-富亮氨酸重复序列（NLRs），它们与toll样受体具有共同特征，这些受体在先天免疫反应中是不可或缺的。低温pyrin在先天免疫中的作用正在研究中，低温pyrin已被证明可以感知多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对多种配体产生特异性的一种机制。本提案的主要目标是描述通过低温霉素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，特别是当它与配体特异性和蛋白质功能相关时。将进行以下实验：1)将利用人类和小鼠模型进行体外和体内研究，以确定冷介导炎症反应的分子机制；2)系统研究宿主-病原体反应，确定fcas相关crypyrin突变对小鼠和人体外单核/巨噬细胞反应以及小鼠体内全身反应的影响；3) crypyrin异构体的表达模式、功能和配体特异性将被研究。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，原因如下：1)它将允许开发新的靶向治疗炎症疾病，目前几乎没有有效的治疗方法；2)它可能为提高感染抵抗力的手段提供见解；了解诸如寒冷之类的物理刺激是如何引发炎症的，可能会导致预防感冒引起的疾病的治疗方法。

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.