After completing his M.S. in Biochemistry at the University of Zurich, Switzerland, Tom Kuhn received a Ph.D. in Neurobiology from the University of Zurich, Switzerland, in 1992. Following postdoctoral positions at Colorado State University, he was an Assistant Professor at the University of Montana and joined the University of Alaska Fairbanks as an Assistant Professor in 2004.
RESEARCH INTERESTS OF THE KUHN LABORATORY
The primary research of the laboratory aims at understanding the role of Rho-subfamily small GTPases, in particular Rac1A, as pivotal regulators of actin filament dynamics and redox homeostasis in central nervous system (CNS) neurons. Disruptions of actin filament dynamics and/or redox status are universally associated with acute CNS injuries and many chronic neurodegenerative CNS disorders. Although axonal growth cones, the tips of elongating axons, are capable of navigating considerable distances prior to establishing connection with their targets during development, they fail to regenerate lost connections following acute axonal injury. Motility, adhesion, and sensory capacity of neuronal growth cones all reside within filopodia and lamellipodia, two morphological structures located at the leading edge of growth cones. The dynamics of both filopodia and lamellipodia result from a continuous reorganization of actin filaments in response to growth inhibitory and growth promoting molecular cues. A strong, progressively spreading inflammation typically follows acute CNS injuries and accompanies many chronic neurodegenerative CNS disorders. This inflammatory reaction causes severe oxidative damage to cellular proteins and lipids due to an increased production of reactive oxygen species (ROS) and ultimately a loss of the neuronal redox homeostasis. Key questions we are addressing include the function of Rrac1A in neuronal redox signaling, the identity and regulation of the source of ROS potentially a neuronal NADPH oxidase activity, and antioxidant enzymatic systems in neuronal plasma membranes. Experimental approaches utilized in the lab include viral mediated gene transfer, state-of-the-art light and fluorescence microscopy techniques, and a broad range of molecular biological and biochemical methods.
Alaska Wild Blueberries and Neuroinflammatory Signaling: Disrupting NADPH oxidase Assembly in Lipid Rafts
Thomas B. Kuhn, Sally J. Gustafson, Kriya L Dunlap, Shane A. Rideout, Brian M. Barth
University of Alaska Fairbanks, Department of Chemistry and Biochemistry, 900 Yukon Drive, Fairbanks, AK 99775. Grant support (NIH U54 NS41069 and USDA 2006-06039)
Our research focuses on Mg2+-dependent neutral sphingomyelinase (nSMase) and NADPH Oxidase (NOX), two membrane enzymes, implicated in the formation of the lipid messenger ceramide and ROS. Inflammatory mediators and reactive oxygen species (ROS) increase neuronal stress and play key roles in the progression of most acute and chronic neurodegenerative pathologies as well as normal aging. Accumulation of ceramide through nSMase activity instigates the formation of lipid rafts in association with the actin cytoskeleton and subsequent organization of stress signaling cascades.
The lipid messenger ceramide in addition to supporting lipid raft formation also increases oxidative stress by stimulating the functional assembly of NOX in lipid rafts. Both ceramide and ROS compromise proper actin dynamics in neuronal cells, which is a prerequisite for fundamental process including plasticity, ion channel function, and gene expression. We found that Alaska wild blueberries extracts (BBX) potently inhibit both nSMase and NOX activity. Notably, inhibitory potency was not linked to antioxidant capacity but more likely attributed to a disruption of lipid raft formation. Isolation and identification of inhibitory compounds in BBX could improve our understanding of neuroinflammatory signaling mechanisms, and provide promising insight into new therapeutic avenues to prevent neurodegeneration.
Alaska Wild Bog Blueberries and Neuroinflammation
Inflammation in the central nervous system (CNS) greatly contributes to cognitive decline in disorders such as Alzheimer’s as well as normal aging. A persistent inflammation and its mediators are harmful to neuronal cells and ultimately lead to a loss of neuronal cells and thus function. Diets rich in fruit and vegetables have long been recognized for the tremendous health benefits for the ailing CNS. This potency was largely attributed to the high content of antioxidant compounds present in fruit and vegetables. More recent studies demonstrated biological activities of natural compounds beyond these features suggesting direct actions to enhance stress protection. Our research revealed that Alaska Wild Bog Blueberries contain compounds with little antioxidant capacity yet great potency to interfere with the detrimental effects of inflammation on neuronal cells.