This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Increased modification of proteins by O-GlcNAc is associated with insulin resistance in Diabetes and has been linked to insulin signaling defects. Preliminary evidence shows that the beta subunit of the insulin receptor itself is modified by O-GlcNAc in adipocytes. Dr. Youngren of the Diabetes Center at UCSF along with Dr. Goldfine have linked insulin resistance in several animal models with defective activation of the insulin receptor tyrosine kinase. This collaboration is for the purpose of detecting and mapping sites of O-GlcNAc on the insulin receptor. The Insulin receptor from normal and insulin resistant skeletal muscle will be immunuprecipitated and its state of O-GlcNAc modification monitored by western blotting. A technique involving beta-elimination/Michael addition using DTT (BEMAD) will be applied to gel excised samples for the purpose of mapping O-GlcNAc sites. Additionally, more global proteomic site-mapping using BEMAD will be undertaken on skeletal muscle of normal vs. muscle from high-fat fed, insulin resistant rats. The results will provide sites of potential post-translational regulatory importance in insulin signaling and insulin resistance.
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