Professor, Department of Cell Biology
Professor, Department of Ophthalmology
Assoc Director Oklahoma Center for Neuroscience
Director, DMEI/NEI Image Acquisition and Analysis Core Facility
B.S., Biology, Sienna College, Loudonville, New York
Ph.D., Cellular and Molecular Biology, State University New York at Buffalo, New York
Postdoctoral Training, Molecular Neurobiochemistry, Mental Retardation Research Center, UCLA School of Medicine Los Angeles, California
Association for Research in Vision and Ophthalmology (ARVO)
American Society of Biological Chemists & Molecular Biologists (ASBCMB)
American Association for the Advancement of Science (AAAS)
International Society of Experimental Eye Research (ISER)
Photoreceptor cells are incessantly bombarded with photons of light which, along with their high rate of oxygen metabolism, continuously exposes them to elevated levels of toxic reactive oxygen intermediates (ROI). Our data show that vacancy engineered, mixed valence state, cerium oxide nanoparticles (Nanoceria particles) scavenge ROI in vitro and prevent increases in the intracellular concentrations of ROI in primary cell cultures of rat retina. Most significantly, they prevent ROI induced blindness in rats. These data suggest the nanoceria particles may be effective in inhibiting the progression of ROI-induced cell death such as occurs in macular degeneration, retinitis pigmentosa, and other blinding diseases as well as the ROI-induced death of other cell types in diabetes, Alzheimer's Disease, atherosclerosis, stroke, etc. The use of nanoceria particles as direct therapy for multiple diseases represents a novel strategy and suggests they may represent a unique platform technology.
Many neurodegenerative diseases are known to occur and progress because of oxidative stress, the presence of reactive oxygen species (ROS) in excess of the cellular defensive capabilities. Age related macular degeneration (AMD), diabetic retinopathy (DR) and inherited retinal degeneration share ROS as a common node upstream of the blinding effects of these diseases. Knockout of the Vldlr gene results in a mouse that develops intraretinal and subretinal neovascular lesions within the first month of age and is an excellent model for a form of AMD called retinal angiomatous proliferation (RAP). Cerium oxide nanoparticles (nanoceria) catalytically scavenge ROS by mimicking the activities of superoxide dismutase and catalase. A single intravitreal injection of nanoceria into the Vldlr-/- eye was shown to inhibit: the rise in ROS in the Vldlr-/- retina, increases in vascular endothelial growth factor (VEGF) in the photoreceptor layer, and the formation of intraretinal and subretinal neovascular lesions. Of more therapeutic interest, injection of nanoceria into older mice (postnatal day 28) resulted in the regression of existing vascular lesions indicating that the pathologic neovessels require the continual production of excessive ROS. Our data demonstrate the unique ability of nanoceria to prevent downstream effects of oxidative stress in vivo and support their therapeutic potential for treatment of neurodegenerative diseases such as AMD and DR.
Methods used - For live animal longitudinal studies on the same animal over time, electroretinography (ERG) for retinal function; optical coherence tomography (OCT) for edema and retinal degeneration; fundoscopy for imaging retinal/choroidal vasculature and leakage; Visual Optomotor Task Assessment: The OptoMotry System for assessing rodent visual acuity and contrast sensitivity. These projects may also involve isolation of plasmid DNA, cloning, subcloning, restriction enzymes, Southern's, Northern's, Yeast two hybrid screen, Western's, electrophoretic mobility shift assays, the polymerase chain reaction(PCR), RTPCR, 1-D and 2-D gel electrophoresis, protein purification, transfections, primary cell culture of mammalian neurons, immunocytochemistry, in vivo transfection, siRNA, fluorescence microscopy, confocal microscopy, in situ hybridization, preparative electrophoresis and the detection and functional evaluation of Nanoceria particles.
Zhou, X., Wong, L.L., Karakoti,A.S., Seal,S. and McGinnis, J.F. (2011) Nanoceria Inhibit the Development and Promote the Regression of Pathologic Retinal Neovascularization in the Vldlr knockout mouse. PLoS ONE. Journal - In Process.
Kong, L., Cai, X., Zhou, X., Wong, L.L., Karakoti, A.S., Seal, S. and McGinnis, J.F. (2011) Nanoceria Extend Photoreceptor Cell Lifespan in Tubby Mice by Modulation of Apoptosis/Survival Signaling Pathways. Neurobiology of Disease. Journal - In Process.
Kong, L., Zhou, X., Li, F., Yodoi, J., McGINNIS, J.F. and Cao, W. (2010) Neuroprotective Effect of Over Expression of Thioredoxin on Photoreceptor Degeneration in Tubby Mice. Neurobiology of Disease; 38: 446-455. PMID: 20298786; PMCID: PMC2919840
Kong, L., Chen, G., Zhou, X., McGinnis, J.F., Li, F., Cao, W. Molecular mechanisms underlying cochlear degeneration in the tubby mouse and the therapeutic effect of Sulforaphane. Neurochem International 54, 172-179, 2009.
Chen, J., Patil, S., Seal, S., McGinnis, J.F. Nanoceria Particles Prevent ROI-Induced Blindness. Adv. Exp. Med. Biol. 613-53-59, 2008
Chen, J., Wu, M., Sezate, S.A., Matsumoto, H., Ramsey, M. and McGINNIS, J.F. (2008) Interaction of Glyceraldehyde-3-Phosphate Dehydrogenase in the Light-Induced Rod Alpha-Transducin Translocation. J Neurochem; 104:1280-1292. PMID: 18028335.
Chen, J., Wu, M., Sezate, S.A. and McGINNIS, J.F. (2007) Light Threshold-Controlled Cone Alpha-Transducin Translocation. Investigative Ophthalmology and Vision Science; 48:3350-3355. PMID: 17591908.
Chen J, Patil S, Seal S, McGinnis JF. Rare Earth Nanoparticles Prevent Retinal Degeneration Induced by Intracellular Peroxides. Nature Nanotechnology 2006; 1: 142-150.
Sampath, A.P., Strissel, K.J., Elias, R., Arshavsky, V.Y., McGinnis, J.F., Chen, J., Kawamura, S., Rieke, F., Hurley, J.B. Recoverin Improves Rod-Mediated Vision by Enhancing Signal Transmission in the Mouse Retina. Neuron. 46(3): 413-420, 2005.
Kong, L., Li, K., Soliman, C., Li, S., Elias, R.V., Zhou, X., Lewis, D.A., McGinnis, J.F. and Cao, W. Bright Cyclic Light Accelerates Photoreceptor Cell Degeneration in Tubby Mice. Neurobiology of Disease 2006 21: 468-477.
Gilmour MA, Cardenas MR, Blaik MA, Bahr RJ, McGinnis JF. Evaluation of a comparative pathogenesis between cancer-associated retinopathy in humans and sudden acquired retinal degeneration syndrome in dogs via diagnostic imaging and western blot analysis. Am J Vet Res 2006; 67: 877-881.
Elias, R.V., Sezate, S.S., Cao, W. and McGinnis, J.F. Temporal Kinetics of the Light/Dark Translocation and Compartmentation of Arrestin and [alpha]-Transducin in Mouse Photoreceptor Cells. Molecular Vision 16:672-681, 2004.
Yu, X., Rajala, R.V., McGinnis, J.F., Li, F., Anderson, R.E., Yan, X., Li, S., Elias, R. and Cao. W. Involvement of Insulin/PI3K/Akt Signal Pathway in 17ß-Estradiol-Mediated Neuroprotection. Journal of Biological Chemistry, 279(13): 13086-13094, 2004.
McGinnis, J.F., Matsumoto, B., Whelan, J.P. and Cao, W. Cytoskeleton Participation in Subcellular Trafficking of Signal Transduction Proteins in Rod Photoreceptor Cells. Journal of Neuroscience Research 67:290-297, 2002.
Cao, W., Tombran-Tink, J., Weiheng, C., Elias, R., Mrazek, D., Sezate, S. and McGinnis, J.F. In Vivo Protection of Photoreceptors from Light Damage by Pigment Epithelium-Derived Factor. Investigative Ophthalmology and Vision Science 42:1646-1652, 2001.
Chen, W., Cao, W., Achyuthan, A.M. and McGinnis, J.F. In Vitro Inhibition of Anti-Recoverin Immunoglobulin-Mediated Death Mammalian Photoreceptor Cells. Journal of Neuroscience Research 63:116-123, 2001.
Dean A. McGee Eye Institute
Department of Ophthalmology
608 Stanton L. Young, Blvd.
Oklahoma City, OK 73126-0901
Phone: (405) 271-3692
Fax: (405) 271-3721
CV - James McGinnis, Ph.D.