Selected Grantee Publications
Lipid Droplets and Peroxisomes Are Co-Regulated to Drive Lifespan Extension in Response to Mono-Unsaturated Fatty Acids
Papsdorf et al., Nature Cell Biology. 2023.
https://www.nature.com/articles/s41556-023-01136-6
Investigators studied the mechanism by which mono-unsaturated fatty acids (MUFAs) extend longevity. They found that MUFAs upregulated the number of lipid droplets in fat storage tissues of Caenorhabditis elegans, and increased lipid droplets are necessary for MUFA-induced longevity and predicted remaining lifespan. Lipidomics data revealed that MUFAs modify the ratio of membrane lipids and ether lipids, which leads to decreased lipid oxidation in middle-aged individuals. MUFAs also upregulate peroxisome number. A targeted screen revealed that induction of both lipid droplets and peroxisomes is optimal for longevity. This study opens new interventive avenues to delay aging. Supported by ORIP (S10OD025004, S10OD028536, P40OD010440), NIA, NCCIH, NIDDK, and NHGRI.
A Gut-Restricted Glutamate Carboxypeptidase II Inhibitor Reduces Monocytic Inflammation and Improves Preclinical Colitis
Peters et al., Science Translational Medicine. 2023.
https://www.science.org/doi/10.1126/scitranslmed.abn7491
Many patients with moderate-to-severe inflammatory bowel disease (IBD) do not have adequate disease control, and glutamate carboxypeptidase II (GCPII) offers a promising target for therapeutic development. Researchers generated a class of GCPII inhibitors. They demonstrated that the inhibitor reduced monocytic inflammation in mice and protected against the loss of barrier integrity in primary human colon epithelial air–liquid interface monolayers. Their findings suggest that local inhibition of GCPII could be applied for the development of IBD therapeutics. Supported by ORIP (K01OD030517, T32OD011089), NIGMS, and NCCIH.
Disentangling the Link Between Zebrafish Diet, Gut Microbiome Succession, and Mycobacterium chelonae Infection
Sieler et al., Animal Microbiome. 2023.
https://pubmed.ncbi.nlm.nih.gov/37563644/
Despite the long-established importance of zebrafish (Danio rerio) as a model organism and their increasing use in microbiome-targeted studies, relatively little is known about how husbandry practices involving diet impact the zebrafish gut microbiome. Given the microbiome's important role in mediating host physiology and the potential for diet to drive variation in microbiome composition, the authors sought to clarify how three different dietary formulations that are commonly used in zebrafish facilities impact the gut microbiome. They report that diet drives the successional development of the gut microbiome, as well as its sensitivity to exogenous exposure. Consequently, investigators should carefully consider the role of diet in their microbiome zebrafish investigations, especially when integrating results across studies that vary by diet. Supported by ORIP (R24OD010998) and NIEHS.
De Novo Protein Fold Design Through Sequence-Independent Fragment Assembly Simulations
Pearce et al., PNAS. 2023.
https://doi.org/10.1073/pnas.2208275120
Researchers developed an automated open-source program, FoldDesign, to create high-fidelity stable folds. Through sequence-independent replica-exchange Monte Carlo simulations and energy force field optimalization of secondary structure, FoldDesign can render novel areas of protein structure and function space that natural proteins have not reached through evolution. These completely different yet stable structures replicate natural proteins’ characteristics with closely matching buried residues and solvent-exposed areas. This work demonstrates a strong potential of creating desired protein structures with potential clinical and industrial applications. Supported by ORIP (S10OD026825), NIAID, NCI, NIEHS, and NIGMS.