Title of project

Molecular and Physiological Regulation of the Salt-inducible Kinase in Control of Hepatic Gluconeogenesis

Abstract

Blood glucose concentration is tightly controlled in healthy humans to prevent the toxic effects of prolonged hyperglycemia and the acute debilitating effects of hypoglycemia. Two vital components to this control are the suppression of hepatic glucose output following a meal, and the induction of hepatic glucose output during prolonged fasting. Our Lab previously demonstrated that salt-inducible kinases (SIK) play an important role in the regulation of gluconeogenesis in hepatocytes in vitro. SIKs are inactivated by glucagon through phosphorylation by cAMP-dependent protein kinase A (PKA), leading to dephosphorylation of transcriptional co-activators (e.g., CRTCs, HDACs) and resulting in enhanced gluconeogenic gene expression and glucose production. The overarching goal of this project is to investigate the role that SIK play in hepatic gluconeogenesis in vivo and elucidate the molecular mechanism by which the glucagon-cAMP-PKA signaling regulates SIK. To establish if pharmacological inhibition of SIK results in hyperglycemia in vivo, I will examine the effect of orally available selective SIK inhibitor in mice ectopically expressing either SIK wild-type or inhibitor-resistant mutant in the liver. To determine the role for a specific SIK isoform in control of gluconeogenesis and glucose homeostasis, I will employ an Affinity directed PROtein Missile (AdPROM) system to rapidly degrade SIK protein specifically in mouse liver. I will perform Proximal Ligation Assay, which permits visualization and quantification of protein-protein interactions, to test the hypothesis that SIK phosphorylation by PKA promotes conformational change leading to altered proximity between SIK and its substrates. This work will deepen our understanding of molecular signaling control of hepatic gluconeogenesis, and may lead to identification of new drug target or small molecules for the treatment of metabolic disorders such as type 2 diabetes.