FOEDRC Announces New Pilot Grant Recipients (September 2017-2018)

The Fraternal Order of Eagles Diabetes Research Center 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.

A total of 43 researchers from across the UI campus submitted meritorious proposals that underwent a comprehensive two stage review.  The review panel had a challenging time to identify three proposals for funding from such a competitive field. Three applicants were selected to receive $50,000 to support their research proposal, with the possibility for a second year of funding, for a total of $100,000 over a two-year period.

The 2017-2018 recipients are:

Songhai Chen, MD, PhD
Associate Professor of Pharmacology and Internal Medicine

Project Title: “Hepatic WDR26:  a Novel Regulator of the PKA Signaling and Glucose Metabolism”

$50,000

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.

N. Charles Harata, MD, PhD
Associate Professor of Molecular Physiology and Biophysics

Project Title: “Acute hypoglycemia and release of neurotransmitter glutamate from brain neurons”

$50,000

Harata Project Summary

Diabetes mellitus (DM) has important effects on the brain. This organ is disproportionally dependent on blood glucose for its energy: in spite of accounting for only 2% of body weight, it consumes about 20% of the energy produced through metabolism. Thus low blood glucose (hypoglycemia) has a strong impact on brain function. When blood glucose levels fall below the physiological range (70-110 mg/dl), the brain undergoes functional and morphological abnormalities. When hypoglycemia is moderate (40-60 mg/dl), cognitive function deteriorates; when it is severe (<40 mg/dl), the patient quickly falls into a coma, and this is accompanied by irreversible neuronal damage and even death of the patient. Hypoglycemia is relatively common among patients, both those with type 1 DM and those with advanced type 2 DM.

The best way to prevent hypoglycemia is to maintain physiological blood glucose levels consistently and effectively, and this involves controlling energy intake, energy expenditure, and insulin levels in the blood. These methods have improved considerably over the last decades. Unfortunately, patients still suffer hypoglycemic episodes due to dynamic natures of blood glucose and insulin levels. In the case of severe hypoglycemia, simply elevating the blood glucose to physiological levels is not sufficient; studies have shown that simple restoration of blood glucose can lead to paradoxical, irreversible loss of brain neurons. In the case of moderate hypoglycemia, the mechanism of neuronal dysfunction remains poorly understood because effective ways of monitoring neuronal functions are not readily available. These points highlight the need to understand the fundamental features of hypoglycemia and the mechanisms whereby it influences neuronal function.

Another situation that is known to lead to neuronal damage is a dramatic increase in the concentration of the amino acid glutamate in a neuron’s surroundings. Although glutamate normally serves as one of the major excitatory neurotransmitters, it becomes a toxin in this context. The glutamate-triggered neuronal damage – known as excitotoxicity – could theoretically play an important role in hypoglycemic brain dysfunction because neurons are thought to secrete glutamate after an episode of hypoglycemia. However, we do not have a clear understanding of the fine details of glutamate release. Major questions relate to: the timing of glutamate release, the site within the neuron from which it is released, how much of it is released, and the mechanisms involved in its release. We also do not know whether the release is reversible or aggravated after repeated hypoglycemic episodes. The goal of the proposed research is to test these features during and after episodes of hypoglycemia. This research is significant because, although blood glucose management has improved, and therefore severe hypoglycemia might become less common, the more common cases of moderate hypoglycemia are less clearly understood. Successful completion of the proposed project will shed light on the mechanisms that contribute to the earliest phase of hypoglycemia – information that will be important in developing novel ways to treat patients subject to episodes of this condition.

Alberto Maria Segre, PhD
Professor, Chair and Gerard P Weeg Faculty Scholar in Informatics

Project Title: “Remote Monitoring of Diabetic Foot Ulcers”

$50,000

Segre Project Summary

Every 30 seconds, someone in the world loses a lower limb to diabetes. Diabetes causes damage to nerves and blood vessels, resulting in loss of sensation and reduced blood flow to the feet. Loss of sensation means diabetics are more likely to develop pressure- and trauma-related injuries, and reduced blood flow inhibits healing of the resulting wounds. Progression of ulcers and infections of surrounding tissue and bone may lead to amputations, disability, and excess healthcare costs. But while the lifetime risk of foot ulcers for patients suffering from diabetes may be as high as 25%, an estimated 50% of diabetic foot ulcers can be prevented with education and patient self-management. With early detection, diabetic foot ulcers can be managed effectively without invasive surgery. Yet, the number of ulcers and amputations remains high. Thus there is a critical need to develop effective approaches for routine foot surveillance, including timely detection of ulcers and wound monitoring.

Our overarching goal is to develop a new approach for remotely monitoring the feet of diabetic patients. Our system exploits the ubiquity of mobile cellphone cameras by texting patients and prompting them to photograph the bottoms of their feet. The photographs are returned to our server via text where they are timestamped, saved to a secure database, and, for now, manually annotated to indicate any visible lesions or ulcers. It is our eventual goal to fully automate the detection of pre-ulcerous lesions or ulcers in these photographs by applying the latest deep-learning methods. Once complete, our system will facilitate the early detection and treatment of diabetic foot ulcers, a leading cause of lower limb amputation. Collaborators include John Femino and Phinit Phisitkul from Orthopaedic Surgery.

Congratulations to all of our FOEDRC Pilot & Feasibility Grant Award Recipients!

Date: 
Thursday, August 24, 2017