David Krizaj did graduate training at New York University with Paul Witkovsky focusing on synaptic signaling between retinal cells and postdoctoral work with David Copenhagen at University of California San Francisco School of Medicine, working on intracellular signaling in photoreceptors. He spent six years as faculty at the at UCSF Dept. of Ophthalmology before joining the Moran Eye Center of the University of Utah in 2007.
The Krizaj lab is interested in "what makes cells alive". The main research model, the retinal photoreceptor, is a complex and highly specialized sensory neuron whose function is to transform light into electrical impulses. This transformation is directly related to our ability to perceive light. Because photoreceptors are very fragile cells and sensitive to mutations they tend to be the first cells to die in retinal degenerations, causing blindness in millions of Americans. Crucially, both perception and transmission of the light signal, as well as photoreceptor degeneration and death are controlled by the calcium ion, making an understanding of its regulation important both from basic science and clinical aspects.
Dr. Krizaj's lab was the first to characterize the identity, function and developmental profile of calcium ATPase (PMCA) transporters that mediate the light response and protect photoreceptors from calcium overload that represents the 'death signal' in degenerating photoreceptors. Using calcium imaging techniques, ERG and patch clamp recordings in knockout animals they showed that loss of specific PMCA isoforms compromises transmission of the visual signal from photoreceptors to the brain.
A second project is focused on the mechanisms through which rod and cone photoreceptors store calcium in intracellular organelles, such as the endoplasmic reticulum and the mitochondria. Dr. Krizaj's lab demonstrated for the first time that dynamic regulation of SERCA transporters and ryanodine receptors that release calcium from internal stores is essential for transmission of the visual signal from photoreceptors. Importantly, rod and cone photoreceptors subserving night and daytime vision were found to express different sets of these calcium transporters and channels. Current work shows that novel calcium-binding proteins are dramatically overexpressed during blinding diseases, representing an ideal target for therapeutic interventions.
Taken together, these studies, funded by the National Eye Institute, Research to Prevent Blindness and other private foundations show that the living photoreceptor cell is an intricate polarized cell which coordinates its metabolism, light adaptation, gene expression, synaptic transmission as well as cell death through calcium fluxes mediated by calcium signaling proteins and organelles localized to specialized subdomains. The goal of future research is to understand how these processes are regulated dynamically during the light response and how they can be modulated to alleviate the degeneration process.
Education: Ph.D., New York University, New York
Academic Appointments: Associate Professor, Ophthalmology, University of Utah School of Medicine.
Sample of major publications from the Krizaj lab
Szikra T. and Krizaj D. 2007. Calcium signals in inner segments of photoreceptors. In: The Visual Transduction Cascade: Basic and Clinical Principles; Eds J. Tombran-Tink and C. Barnstable, Humana Press, Totowa, NJ. In the press
Szikra T. and Krizaj D. 2007. Calcium channels, mitochondria and endoplasmic reticulum regulate calcium signaling in photoreceptors. Visual Neuroscience, in the press
Duncan J, Yang H, Doan T, Silverstein B, Murphy G., Nune G, Liu X, Copenhagen D.R., Rieke, F., Tempel B.L. and Krizaj D. 2006. Scotopic visual signaling in the mouse retina is modulated by high affinity plasma membrane calcium extrusion Journal of Neuroscience, 26, 7201-7211
Szikra T. and Krizaj D. 2006. The dynamic range and domain-specific signals of intracellular calcium in photoreceptors. Neuroscience, 141, 143-155
Krizaj D., Lai T. and Copenhagen, D.R. 2003. Ryanodine stores and calcium regulation in inner segments of salamander rods and cones. Journal of Physiology 547, 761-774
Krizaj D., Bao J.X., Schmitz Y., Witkovsky P. and Copenhagen D.R. 1999. The action of caffeine on glutamate release at the rod photoreceptor synapse. Journal of Neuroscience 19, 7249-7261
Krizaj D. and Copenhagen D.R. 1998. Compartmentalization of calcium extrusion mechanisms in the outer and inner segments of photoreceptors. Neuron 21, 249-256