The role of cryopyrin in autoinflammatory diseases

描述(由申请人提供)：家族性感冒自体炎症综合征(FCAS)是免疫系统对物理刺激做出反应的一个例子。这项申请寻求拓宽我们对炎症的分子机制的知识，使用FCAS作为模型。这种疾病为研究炎症提供了一个独特的机会，因为我们最近发现了与FCAS有关的基因(CIAS1)和蛋白质(低温比林)。许多积极性很高的患者都可以参与，FCAS炎症症状可以在受控环境(冷挑战)中诱发和测量。与FCAS一样，许多炎症性疾病通常很少有安全有效的治疗方法，因此我们的研究最终可能导致炎症性疾病的新疗法，具有重要的临床和科学意义。本项目的主要目的是阐明低温比林的正常和异常结构和功能，以便更好地了解FCAS和其他炎症性疾病的生理学基础。这些目标将利用已建立的分子遗传学技术、产生抗体的新的和已建立的方案以及先进的成像技术来实现。 本应用的具体目的是：(1)进一步研究FCAS的遗传学，包括鉴定其他突变及其与临床特征的相关性；(2)描述CIAS1基因在组织、白细胞和细胞系中的表达；(3)通过评估信号通路和与之相互作用的蛋白质，表征低温比林的结构、定位和表达，并初步研究低温比林的功能；(4)通过观察和收集临床样本，确定在实验性冷室挑战时这些患者发生炎症的机制。这些目标的实现将提高我们对FCAS炎症以及其他炎症性疾病的理解。

DESCRIPTION (provided by applicant): Familial cold autoinflammatory syndrome (FCAS) is an example of the immune system's response to physical stimuli. This application seeks to broaden our knowledge of the molecular mechanisms of inflammation, using FCAS as a model. This disease provides a unique opportunity to study inflammation because we recently identified the gene (CIAS1) and protein (cryopyrin) responsible for FCAS. Many highly motivated patients are available for participation, and FCAS inflammatory symptoms can be elicited and measured in a controlled environment (cold challenge). As in FCAS, frequently there are few safe and effective treatments for many of the inflammatory disorders, so our research which may ultimately lead to novel therapeutics for inflammatory disorders is important clinically as well as scientifically. The primary objective of this project is to elucidate the normal and abnormal structure and function of cryopyrin in order to develop a better understanding of the physiologic basis of FCAS and other inflammatory diseases. These aims will be accomplished utilizing established molecular genetics techniques, new and established protocols for generation of antibodies, and advanced imaging techniques. The specific aims of this application are (1) further investigation of the genetics of FCAS including identification of additional mutations and correlation of these mutations with clinical features, (2) delineation of the CIAS1 gene expression in tissues, leukocytes, and cell lines (3) characterization of the cryopyrin protein structure, localization, and expression and initial studies of the function of cryopyrin by evaluating signaling pathways and proteins with which it interacts, and (4) determination of the mechanisms of inflammation that occur with an experimental cold room challenge in these patients by observation and collection of clinical samples. The achievement of these goals will improve our understanding of inflammation in FCAS as well as other inflammatory disorders.