This proposal focuses on the study of a protein that appears to regulate inflammation, namely CIAS 1. This protein, also known as cryopyrin, is a member of a newly-described family of NBD-LRR proteins that we have identified as the CATERPILLER family. CIAS 1 mutations have been genetically associated with several autoinflammatory diseases, such as Muckle Wells Syndrome (MWS), familiar cold autoimmune syndrome (FCAS), and Chronic Infantile Neurological Cutaneous and Articular Syndromes (CINCA)/neonatal-onset multisystem inflammatory disease (NOMID). Initial characterization of the relevance of CIAS 1 has focused on its role in TLR signaling pathways and host innate immune defense mechanisms. CIAS 1 has been shown to be expressed primarily in cells of myeloid lineage. Data from our laboratory show that several agonists of the TLR pathway induce CIAS 1 expression. Initial biochemical characterizations of CIAS 1 function have been performed by transfecting expression plasmids into non-myeloid cells. These studies indicate a negative regulatory role on NFkappaB activity and therefore a role in the control of inflammatory responses. This is reminiscent of the recently described IRAK-M molecule, which is a negative regulator of endotoxin response and is induced by TLR agonist. The negative regulatory role of CIAS 1 is consistent with the presence of overzealous inflammation in autoimmune diseases where it is mutated. The objective of this proposal is to examine the function of CIAS 1 in controlling NFkB activity and therefore inflammation. To accomplish this goal, myeloid cell lines lacking CIAS 1 will be created using RNA interference (RNAi) technology. Subsequently, changes in CIAS 1 regulation of NFkappaB and the activity of inflammatory regulators in these cell lines will be examined. Lastly, mutant CIAS 1 clones recapitulating disease-associated genetic alterations will be created by site-directed mutagenesis. Consequences of these mutations on the control of NFkappaB activity and inflammation will be assessed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI061059-02
Application #
6898391
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Winter, David B
Project Start
2004-06-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$181,045
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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