The innate immune system comprises several classes of pattern recognition receptors, including Toll- like receptors (TLRs), NOD-like receptors (NLRs), and RIG-1-like receptors (RLRs). TLRs recognize microbes on the cell surface and in endosomes, whereas NLRs and RLRs detect microbial components in the cytosol. In some autoinflammatory conditions, abnormalities in NLR signaling pathways are involved in pathogenesis, as exemplified by cryopyrin mutations associated with three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multiple-system inflammatory disease. Cryopyrin forms a multi-protein complex termed 'the inflammasome', which contains the ASC and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-12 into an active form, the secretion of which leads to a potent inflammatory response. Recent studies have demonstrated that cryopyrin mutations found in patients with autoinflammatory disease function as activating mutations resulting in enhanced IL-12 secretion. In addition, pyrin, the product of familial fever (FMF), negatively regulates the cryopyrin inflammasome signaling. Results from our laboratory and others show that cryopyrin and ASC play a critical role in the response of macrophages to microbial components, bacteria and viruses. Altogether, the central hypothesis on which this proposal is based is that dysregulated cryopyrin inflammasome signaling is a primary contributor to the spectrum of autoinflammatory diseases. To address our hypotheses and to understand the role of innate immune responses in inflammatory and infectious diseases, we propose to study the role of cryopyrin/ASC signaling pathway in inflammatory disease, host defense and regulation of cytokine/chemokine secretion. The proposed studies will help development of new molecular insights into the molecular and cellular mechanisms regulating infection and autoinflammation, thus leading to novel therapeutic targets for inflammatory and infectious diseases.

Public Health Relevance

The studies proposed will provide novel insights into the physiological role of the innate immune system/cryopyrin signaling in inflammation, host defense and into the pathogenesis of autoinflammatory syndromes thus leading to novel therapeutic targets for inflammatory and infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR056296-03S1
Application #
8231791
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Mancini, Marie
Project Start
2008-09-15
Project End
2013-07-31
Budget Start
2011-03-01
Budget End
2011-07-31
Support Year
3
Fiscal Year
2011
Total Cost
$46,791
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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