The nicotinamide adenine dinucleotide (NAD+) dependent deacetylase SIRT1 has a wide-range of biological functions including chromatin structure maintenance, metabolism and the regulation of healthspanlifespan in the absence of disease. In mice, whole body overexpression of SIRT1 promotes characteristics similar to calorie-restriction such as a decrease in the incidence of age-related diseases including diabetes and cardio vascular disorders. SIRT1 has therefore drawn attention in this regard as a target for drug design, as a molecule that activated SIRT1 could treat multiple age-related diseases impacting global health and economics. Recent work with SIRT1 activators has been mixed. Preliminary work from our laboratory has identified mono-unsaturated fatty acids (MUFAs) as endogenous activators of SIRT1 deacetylase activity. Moreover, MUFA-mediated activation of SIRT1 depends upon the SIRT1 substrate with oleate (a MUFA) causing a 2.8-fold increase in SIRT1 activity towards PGC-1a, while activity towards another other peptide substrate, H3, showed less robust activation. Thus, these studies have identified oleate as the first endogenous, non-substrate activator of SIRT1 that alters SIRT1 substrate recognition. The objective of the current proposal is to determine the properties of SIRT1 targeting and identify which targets respond to ligand activation. We hypothesize that SIRT1 targets specific protein sequences constitutively, while ligands selectively target SIRT1 to distinct protein/peptide sequences. We will evaluate SIRT1 motif and sequence specificity via a state of the art proteomics pipeline. Results from this proposal will be significant in providing fundamental structural and mechanistic data that can be used for targeted drug design leading to advancements in age-related diseases including diabetes and cardiovascular disorders.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|