Federal Project Grant Award Summary

The National Institute of General Medical Sciences (NIGMS) awarded the University of California Irvine $365,267 through the Biomedical Research and Research Training program (CFDA 93.859) for a Project Grant commencing July 1, 2026, and concluding March 31, 2031. This award funds fundamental research into the macromolecular structure and mechanism of the NLRP3 innate immune receptor complex. The research will elucidate how NLRP3 recognizes and processes oxidized mitochondrial deoxyribonucleic acid (DNA) as a danger signal, a poorly understood mechanism central to inflammasome assembly and implicated in chronic inflammatory diseases including gout, Alzheimer's disease, and type 2 diabetes.

The project delivers knowledge products through integrated structural and biochemical investigations, including cryo-electron microscopy (cryo-EM) structural characterization of NLRP3-DNA interactions, mapping of critical residues through mutagenesis studies, and cellular mechanistic validation using CRISPR/Cas9-engineered macrophage models. The research will determine how small-molecule inhibitors modulate NLRP3's enzymatic activity and suppress inflammasome activation, providing both fundamental scientific insights into innate immune signaling and protein-nucleic acid interfaces and potential therapeutic pathways for inflammatory disease intervention. These deliverables align directly with NIGMS's mission to support basic biomedical research that advances understanding of biological processes underlying disease mechanisms.