Songhai Chen receives FOEDRC Pilot & Feasibility Grant

The Fraternal Order of Eagles Diabetes Research Center (FOEDRC) at The University of Iowa, Carver College of Medicine, is pleased to announce the results of its seventh round of pilot and feasibility research grants.  These grant awards fund innovative pilot projects by early career investigators who are entering the diabetes research field, or established investigators with innovative ideas that focus their research program and represent a new direction that addresses important questions in diabetes research. The goal of the program is to generate data that will enable awardees to compete for peer-reviewed national funding for projects that show exceptional promise. These pilot project research grants are supported by gifts from the Fraternal Order of Eagles, which now endow this grant program.

Songhai Chen photoSonghai Chen, MD, PhD, Associate Professor of Pharmacology and Internal Medicine received a FOEDRC Pilot & Feasibility Grant.  Dr. Chen was one of three applicants selected to receive $50,000 to support his research proposal entitled, “Hepatic WDR26:  a Novel Regulator of the PKA Signaling and Glucose Metabolism” with a possibility for a second year of funding.   

Chen Project Summary

Hyperglucagonemia is present in every form of diabetes, and glucagon signaling is essential for the development of hyperglycemia and metabolic disorders in diabetes. Glucagon elevates the blood glucose level primarily by increasing hepatic glucose production through glycogenolysis and gluconeogenesis. It binds to G-protein coupled receptors on hepatocytes to activate cAMP/PKA phosphorylations of diverse enzymes and transcription factors. Glucagon and/or PKA signaling has been proposed as a new target for antidiabetic drugs. To develop efficient and safe ways to target hepatic cAMP/PKA signaling in diabetes, the process must first be well understood.

 For a variety of cellular processes and tissues, PKA activity is spatiotemporally regulated by a group of anchoring proteins called A kinase anchoring proteins (AKAPs). In the liver, an AKAP that regulates cAMP/PKA signaling for hepatic glucose production has not been identified yet; however, recently, we identified a novel scaffolding protein, WDR26, that may function as a PKA-tethering AKAP. We showed WDR26 interacts with G proteins to facilitate transduction of signals to downstream effectors. Our preliminary studies in vitro and in vivo (using primary hepatocytes and a liver-specific WDR26 knockout mouse, respectively) showed WDR26 controlled PKA signaling by tethering it to its upstream activators and downstream effectors. Hepatic WDR26 was required during glycogenolysis and gluconeogenesis to maintain the normal blood glucose level and was upregulated in high-fat-diet-induced diabetes, which contributes to hyperglycemia and the development of fatty liver. This strong preliminary data led us to hypothesize that hepatic WDR26 is a hitherto unrecognized AKAP that orchestrates PKA signaling to regulate hepatic glucose production, and that WDR26 overexpression contributes to hyperglycemia in diabetes and development of a fatty liver. In this proposal, we will investigate how WDR26-regulated PKA signaling controls hepatic glucose production (Aim 1); and the mechanisms by which WDR26 interacts with PKA and regulates the dynamics of PKA signaling (Aim 2). Results from these studies should generate critical preliminary data for the submission of a highly competitive R01 application investigating WDR26 as an unrecognized PKA anchoring protein, and a novel target for new diabetes therapies.

Thursday, August 24, 2017