The role of cryopyrin in autoinflammatory diseases

隐热蛋白在自身炎症性疾病中的作用

• 批准号: 6937116
• 负责人: HAROLD M HOFFMAN
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6937116
• 关键词: autoimmune disorder; blood proteins; clinical research; cold temperature; family genetics; gene mutation; human subject; inflammation; molecular pathology; nuclear factor kappa beta; protein protein interaction; protein structure function

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.

描述（由申请人提供）：家族性冷自身炎症综合征（FCA）是免疫系统对物理刺激的反应的一个例子。该应用旨在以FCA作为模型来扩大我们对炎症分子机制的了解。 该疾病为研究炎症提供了独特的机会，因为我们最近确定了负责FCA的基因（CIAS1）和蛋白质（冷冻蛋白）。许多高度积极进取的患者可以参与，并且可以在受控环境中引起和测量FCAS炎症症状（冷挑战）。就像在FCA中一样，对于许多炎症性疾病，通常很少有安全有效的治疗方法，因此我们的研究最终可能导致炎症性疾病的新型治疗方法在临床上和科学上都很重要。该项目的主要目的是阐明冷冻蛋白的正常和异常结构和功能，以便更好地了解FCA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，用于生成抗体的新方案以及高级成像技术实现。 该应用的具体目的是（1）进一步研究FCA的遗传学，包括识别其他突变以及这些突变与临床特征的相关性，（2）在组织，白细胞和细胞系中CIAS1基因表达的描述，以及细胞系（3）通过Cryopyrin蛋白结构和初始研究的表征和初始研究的表征，以及该杂志的表达和初始研究的表征，以及该功能的表达，并构成了杂草的表达。相互作用，以及（4）通过观察和收集临床样本来确定这些患者在这些患者中发生的寒冷室挑战的炎症机制。实现这些目标将提高我们对FCA和其他炎症性疾病中炎症的理解。