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Principal Investigator: Jiujiu Yu
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2024
Award: $315,809
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Obesity is a chronic progressive disease that leads to the development of heart disease, stroke, and type 2 diabetes, which are among the top ten leading causes of death in the United States. The initiation and progression of obesity-related diseases is strongly associated with chronic low-grade inflammation, and the NLRP3 inflammasome is a key sensor that instigates inflammation in obesity. Targeting NLRP3 inflammasome-mediated inflammation should curb or prevent the disease progression and thus holds therapeutic promise to combat obesity-related diseases. However, effective and safe strategies that specifically inhibit the NLRP3 inflammasome in obesity have not been developed for patient treatment. As such, the long- term goal of our research is to develop a new dietary strategy or therapeutic modality to suppress NLRP3 inflammasome activity and inflammation in obesity and obesity-related diseases. As an initial step, this project will define the role of chive-derived exosome-like nanoparticles (C-ELNs) in suppressing inflammation in obesity. Our pilot studies found that C-ELNs strongly inhibited NLRP3 inflammasome activation in primary macrophages. One of their bioactive molecules, 1,2-dilinoleoyl-sn-glcyero-3-phosphocholine, was identified as an inhibitor of the NLRP3 inflammasome. Oral administration of C-ELNs, started concomitantly with high-fat diet feeding, reduced NLRP3 inflammasome activity and improved metabolic health in the C57BL/6J mice. Building on our preliminary work, this project will test the central hypothesis that C-ELNs contain active biomolecules that inhibit NLRP3 inflammasome activity and ameliorate inflammation in obesity. This hypothesis will be tested through two specific aims: 1) identify active biomolecules in C-ELNs that inhibit NLRP3 inflammasome activity and 2) define the role of C-ELNs and their active biomolecules in suppressing inflammation in obesity. Successful completion of the proposed research be the first step toward the translation of C-ELNs and active biomolecules into an intervention to suppress NLRP3 inflammasome activity and inflammation in obesity. Utilizing dietary ELNs to target the NLRP3 inflammasome is an innovative approach. The unique features of dietary ELNs, including tissue bioavailability, bioactivity, and biomolecule protection and delivery, as well as their abundance in edible plants confer upon them high translational potential.
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