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P.I.:<\/strong> Thomas Hawn, MD, PhD<\/a> Distinguishing beneficial from deleterious inflammation is essential for the development of novel treatment strategies for cystic fibrosis. NLRC4 is a cytoplasmic pattern recognition receptor that detects flagellin and Type III secretion system (T3SS) expressing bacteria and activates the inflammasome, a caspase-1 dependent process that culminates in IL-1\u03b2, IL-18, and eicosanoid release and pyroptotic cell death. Pseudomonas aeruginosa (Pa) is flagellated, expresses a T3SS and stimulates macrophages through several innate immune receptors including Toll-like Receptors (TLRs) and inflammasome receptors such as NLRC4, NAIP, and NLRP3. Recent studies in cystic fibrosis suggest that aberrant inflammasome-dependent IL-1\u03b2 production may cause lung pathology through NLRC4 and NLRP3. Interactions between CFTR (Cystic fibrosis transmembrane conductance regulator)-dependent pathways and inflammasome pathways are poorly understood. These studies raise fundamental questions about the role of the inflammasome in the initiation and propagation of airway inflammation with both beneficial anti-microbial and deleterious immunopathologic consequences. Our preliminary data suggest that rare and common NLCR4 genetic variants regulate inflammasome activation which impairs lung function and contributes to Pa colonization in cystic fibrosis patients. These data raise several critical mechanistic questions with translational impact. In this proposal, we will test our overall hypothesis that human NLRC4 deficiency protects cystic fibrosis patients from lung immunopathology caused by Pseudomonas. We also hypothesize that CFTR and TLR5 functional variants modify NLRC4-dependent inflammasome function in macrophages and clinical outcomes in CF patients. Our long term translational goal is to discover the optimal intervention for an experimental medicine trial with modulation of IL-1\u03b2 and\/or other inflammasome regulators and mediators.[\/et_pb_text][\/et_pb_column][\/et_pb_row][\/et_pb_section]<\/p>\n","protected":false},"excerpt":{"rendered":" P.I.: Steven Kahn, MB, ChB<\/a>
\nProfessor, Medicine, Allergy & Infectious Diseases<\/p>\n
Professor of Medicine
Metabolism, Endocrinology and Nutrition<\/p>