The NLRP3 inflammasome is essential for the production of IL-1? and other pro-inflammatory mediators, and as such is critical in elaborating inflammation in a variety of settings, including infectious diseases, autoinflammatory diseases, and complex diseases characterized by pathological inflammation. In many such diseases, the etiologic agent has been shown to instigate inflammation in a NLRP3 inflammasome-dependent manner. Examples include extracellular ATP released from dying cells, uric acid crystals that accumulate during arthritis, cholesterol crystals in atherosclerotic plaques, various bacterial toxins, and misfolded protein aggregates linked to neurodegenerative diseases. How these diverse molecules activate the NLRP3 inflammasome is not known, and our recent studies implicate a critical role for Calcium (Ca2+) signaling. In this proposal we aim to further elucidat how Ca2+ mobilization regulates activation of the NLRP3 inflammasome, uncover new regulators of the pathway, and integrate current models into one unifying model. This effort would advance basic research in the inflammasome field and identify novel targets for treating the many diseases linked to NLRP3 inflammasome activation.

Public Health Relevance

Understanding how inflammation is triggered is critical for therapeutic intervention in diseases characterized by pathophysiological inflammation, including rare autoinflammatory diseases as well as common diseases such as arthritis, atherosclerosis, and diabetes. Here we seek to elucidate mechanisms that regulate activation of a critical inflammatory pathway implicated in such diseases. We expect that successful completion of this work would reveal one central underlying mechanism that could be targeted therapeutically, with the potential to significantly impact public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI102964-02
Application #
8613434
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
2013-02-15
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$363,375
Indirect Cost
$138,375
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
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Covarrubias, Anthony J; Horng, Tiffany (2014) IL-6 strikes a balance in metabolic inflammation. Cell Metab 19:898-9
Horng, Tiffany (2014) Calcium signaling and mitochondrial destabilization in the triggering of the NLRP3 inflammasome. Trends Immunol 35:253-61
Byles, Vanessa; Covarrubias, Anthony J; Ben-Sahra, Issam et al. (2013) The TSC-mTOR pathway regulates macrophage polarization. Nat Commun 4:2834