Shaodong Guo

The long-term goal of our research is to study the molecular mechanisms of insulin signal transduction, insulin resistance and associated cardiovascular dysfunction, aiming at nutritional and therapeutic intervention for control of metabolic and cardiovascular disorders. My laboratory is focused on the study of cellular signaling and gene transcriptional regulation of metabolic homeostasis that are governed by the PI3K→Akt→FoxO pathway, with the hope of understanding how dysregulation of this pathway in insulin/IGF-1 action causes liver damage, cardiovascular dysfunction, and pancreatic beta cell failure, resulting in diabetes, obesity, and organ failure. Our research encompasses several areas. Firstly, we will decode the mechanism of insulin resistance and associated cardiovascular dysfunction. It is known that excess nutrients cause or accelerate insulin resistance, investigating how nutrient-mediated signaling activates intracellular mediators that attenuate the insulin→IRS→Akt→FoxO signaling pathway will provide a powerful platform for nutritional and therapeutic intervention for the treatment of diabetes and cardiovascular disorders. The discovery of bioactive compounds, functional food, peptides, nucleotides, or stem cells that increase gene expression of IRS or promote FoxO phosphorylation and ubiquitination will promote drug development and provide new insights on nutritional and therapeutic targets. Secondly, we will define the roles of FoxO proteins in insulin signaling and insulin resistance through creation of cell lines and animal models in which FoxO is either eliminated by a genetic “knock-out” or increased by overexpression. This will also include studies utilizing the technique of tissue specific gene inactivation or activation (knock-in) to determine the role of FoxO in various tissues, including classic and non-classic target tissues for insulin action, such as liver and heart. Lastly, we will explore the novel players mediating insulin actions, as well as other hormones including glucagon, in control of energy metabolism and survival. We have taken advantage of IRS and FoxO genetically engineered mouse and cell models with analyses in genomics, proteomics, and metabolomics, to better define the physiological connections between metabolic regulation and FoxO in intracellular signaling networks.

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