Proteome-guided CRISPR identification of insulin sensitivity mediators

Objective

Type 2 diabetes (T2D) is a growing global health epidemic. Insulin resistance promotes T2D, adversely affecting human health, increasing the risk of all-cause mortality, and generating an enormous socioeconomic burden. Skeletal muscle is the major tissue responsible for blood glucose lowering effects of insulin, and thus insulin resistance in this tissue is a primary driver of disease pathology. Exercise is an effective intervention for skeletal muscle insulin resistance, promoting glucose uptake and enhancing insulin sensitivity. However, patient adherence to exercise regimens is low and no T2D therapies directly improve skeletal muscle insulin action. Understanding protein and signaling events that mediate insulin and exercise induced glucose uptake in skeletal muscle is vital for identifying therapeutic targets for insulin resistance and T2D. PRISM aims to identify clinically relevant targets for insulin resistance in skeletal muscle and assess their involvement in regulating glucose uptake. To achieve these aims, I will combine omics, cell biology and physiology approaches. Large-scale protein and signaling analyses of human skeletal muscle in basal, exercise and insulin-stimulated states will be comprehensively integrated with clinical phenotyping to identify therapeutic targets. The function of identified targets in insulin stimulated glucose uptake will be assessed with state-of-the-art CRISPR screens and cell biology approaches. Finally, the physiological role of select targets will be assessed using an innovative and rapid CRISPR knockout animal model. This MSCA has the potential to make a breakthrough in clarifying underlying mechanisms of insulin and exercise signaling, providing insights into novel drug targets for treating T2D.