The role of cryopyrin in autoinflammatory diseases

描述（由申请人提供）：家族性寒冷自身炎症综合征（FCAS）是免疫系统对物理刺激反应的一个例子。本申请旨在扩大我们对炎症分子机制的认识，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负责FCAS的基因（CIAS1）和蛋白质（cryopyrin）。许多积极性很高的患者可以参与，FCAS炎症症状可以在受控环境（冷激）中诱发和测量。与FCAS一样，对于许多炎症性疾病，通常很少有安全有效的治疗方法，因此我们的研究可能最终导致炎症性疾病的新疗法在临床和科学上都很重要。本项目的主要目的是阐明cryopyrin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基础。这些目标将利用已建立的分子遗传学技术、用于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。 本申请的具体目的是（1）进一步研究FCAS的遗传学，包括鉴定额外的突变和这些突变与临床特征的相关性，（2）描绘组织、白细胞和细胞系中的CIAS 1基因表达，（3）表征cryopyrin蛋白结构、定位，以及通过评估信号传导途径和与其相互作用的蛋白质来表达和初步研究cryopyrin的功能，和（4）通过观察和收集临床样品来确定这些患者中实验性冷室挑战发生的炎症机制。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.