The role of cryopyrin in autoinflammatory diseases

University Of California San Diego, La Jolla CA

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Abstract

[unreadable] 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. [unreadable] [unreadable] 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.