Federal Project Grant Award Summary

Boston Children's Hospital received a $124,992 Project Grant from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855), awarded May 15, 2026, with completion targeted for April 30, 2028. The research investigates the priming and activation mechanisms of the NLRP3 inflammasome—a cytosolic protein complex that regulates the release of the proinflammatory cytokine interleukin-1 beta (IL-1B)—with specific focus on understanding how oxidized phospholipids function as sterile signals in driving inflammasome activation in macrophages. During the K99 phase, the research team will employ structural biology, glycoproteomics, and spatial transcriptomics methodologies to dissect the novel regulatory mechanisms controlling inflammasome activity, including the role of NLRP3 glycosylation and metabolic rewiring, and will map the spatial organization of IL-1B-producing macrophages within atherosclerotic lesions.

The R00 phase will extend this conceptual and technical framework to the study of Cryopyrin-Associated Periodic Syndromes (CAPS), a group of rare autoinflammatory diseases caused by NLRP3 gain-of-function mutations. The research hypothesizes that CAPS-associated variants bypass the priming step through loss of inhibitory phosphorylation and competition with glycosylation, and will generate novel inducible models to test these mechanisms. This work addresses the broader research objective of understanding dysregulated inflammasome activation in sterile inflammatory diseases, including atherosclerosis, with anticipated deliverables including identification of key posttranslational modifications controlling inflammasome activity and mechanistic insights applicable to both common and rare inflammatory disease contexts.