University of Virginia Health System

The long-term goal of my lab is to determine the mechanisms of inflammatory-mediated pancreatic islet dysfunction related to diabetes and metabolic disorders. Inflammation and immune responses can lead to destruction of insulin-producing beta cells within islets through the effects of exogenous cytokines or through induction of certain cytokines within the beta cells themselves. We have shown that pro-inflammatory cytokines induce dysfunction in islet handling of intracellular calcium at much lower concentrations than required to measurably disrupt insulin secretion and induce cell death. We are actively investigating possible
source(s) of dysfunctional calcium handling including endoplasmic reticulum stress, mitochondrial disruption, and ion-channel dysfunction using a combination of physiological and molecular approaches. By identifying the physiological impact of cytokines at very low doses, we hope to identify early and reversible steps in islet dysfunction.

We are also developing techniques to assess and improve islet health and function. One project, funded by the Mouse Metabolic Phenotyping Center, involves pre-labeling one set of islets with an inert fluorescent dye to allow simultaneous comparisons of labeled and unlabeled islets under identical conditions. This approach will provide valuable and novel information about dynamic changes in islet metabolic rates, calcium handling, and secretion in response to glucose or other stimuli in order to detect very precise deficiencies or enhancements in islet function. We will utilize this technique to identify precursors of islet dysfunction and to assess potential therapies for diabetes at the islet level.

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