Genomes and Genes
Principal Investigator: R E Marc
Affiliation: University of Utah
Abstract: DESCRIPTION (provided by applicant): A cascade of neuronal and glial transformations are triggered by photoreceptor or retinal pigmented epithelium degenerations. These remodeling processes, initiated prior to the death of photoreceptors and persisting after they are lost, encompass over 30 distinct aberrations including altered glutamate receptor expression, anomalous neurite and synapse formation, anomalous signaling, intraretinal migration and emigration, and neuronal death. Remodeling stands in the way of many proposed therapies. Our program focuses on discovering key remodeling mechanisms for drug discovery, intervention and retinal stabilization in retinitis pigmentosa (RP) and AMD. We will attempt this through three aims: (1) analysis of early cone and bipolar cell deconstruction;(2) exploration of mechanisms of corruptive intrinsic non-visual self-signaling and retinoid-induced axonogenesis;and (3) characterizing remodeling in AMD / AMD-like retinal degenerations. This research fuses advanced cell profiling methods of excitation mapping, computational molecular phenotyping (CMP), and traditional protein mapping with a selection of RP/AMD animal models (guanylate cyclase knockout mice, light-induced retinal degeneration mice, Pde6brd1 mice, rhodopsin P347L transgenic rabbits). We seek definition of key molecular pathologies (e.g. MAPK pathways in cones and bipolar cells, aberrant retinoid processing;emigrant cell profiles) that may serve as drug targets. The goal is to preserve RP and AMD retinas for genetic, molecular, cellular or bionic rescue. Relevance. Loss of neuronal structure and function in remodeling is likely the earliest cause of vision loss in retinal degenerations. These anomalies progressively impede development of therapies. Discovering the mechanisms of the many forms of remodeling may facilitate neuroprotective drug development or identification of existing drugs. PUBLIC HEALTH RELEVANCE: Loss of neuronal structure and function in remodeling is likely the earliest cause of vision loss in retinal degenerations. These anomalies progressively impede development of therapies. Discovering the mechanisms of the many forms of remodeling may facilitate neuroprotective drug development or identification of existing drugs.
Funding Period: ----------------2003 - ---------------2011-
more information: NIH RePORT
- Neural reprogramming in retinal degenerationRobert E Marc
Department of Ophthalmology, John A Moran Eye Center, University of Utah, Salt Lake City, Utah 84132
Invest Ophthalmol Vis Sci 48:3364-71. 2007..The authors sought to explore the functional expression of ionotropic (iGluR) and group 3, type 6 metabotropic (mGluR6) glutamate receptors in late-stage photoreceptor degeneration...
- Restoration of retinal structure and function after selective photocoagulationAlexander Sher
Santa Cruz Institute for Particle Physics, University of California, Santa Cruz, California 95064, USA
J Neurosci 33:6800-8. 2013..This finding extends the previously perceived limits of restorative plasticity in the adult retina and allows for new approaches to retinal laser therapy free of current detrimental side effects such as scotomata and scarring...
- Deimination restores inner retinal visual function in murine demyelinating diseaseMabel Enriquez-Algeciras
Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
J Clin Invest 123:646-56. 2013..Thus, protein deimination and dendritic outgrowth play key roles in visual function and may be a general feature of demyelinating diseases...
- ON cone bipolar cell axonal synapses in the OFF inner plexiform layer of the rabbit retinaJ Scott Lauritzen
Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, Utah 84132, USA
J Comp Neurol 521:977-1000. 2013..Such joint distribution sampling is likely common when targets are sparser than sources and when sources are coupled, as are ON cone bipolar cells...
- Retinal remodelingB W Jones
Department of Ophthalmology, Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA
Jpn J Ophthalmol 56:289-306. 2012..However, all of these insults as well as traumatic insults to the retina result in retinal remodeling. Retinal remodeling is a universal finding subsequent to retinal degenerative disease that results in ..
- Computational molecular phenotyping of retinal sheet transplants to rats with retinal degenerationM J Seiler
Anatomy and Neurobiol Reeve Irvine Research Center, UC Irvine, Irvine, CA 92697 4265, USA
Eur J Neurosci 35:1692-704. 2012....
- Retinal connectomics: towards complete, accurate networksRobert E Marc
University of Utah School of Medicine, Department of Ophthalmology, John A Moran Eye Center, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA Electronic address
Prog Retin Eye Res 37:141-62. 2013..This is but the beginning, as the underlying principles of connectomics are readily transferrable to non-neural cell complexes and provide new contexts for assessing intercellular communication. ..
- Extreme retinal remodeling triggered by light damage: implications for age related macular degenerationRobert E Marc
Ophthalmology, University of Utah, John A Moran Eye Center, Salt Lake City, UT 84132, USA
Mol Vis 14:782-806. 2008..An hypothesis emergent from data analysis is that the LIRD model closely mimics late-stage atrophic age relared macular degeneration (AMD)...
- The Viking viewer for connectomics: scalable multi-user annotation and summarization of large volume data setsJ R Anderson
Department of Ophthalmology, Moran Eye Center, University of Utah, Salt Lake City, UT 84132, U S A
J Microsc 241:13-28. 2011..4) It is capable of applying transformations in real-time. (5) It has an easily extensible user interface, allowing addition of specialized modules without rewriting the viewer...
- Effect of shape and coating of a subretinal prosthesis on its integration with the retinaA Butterwick
Stanford University, Department of Applied Physics, Stanford, CA 94305, USA
Exp Eye Res 88:22-9. 2009..Pillars demonstrated minimal alteration of the inner retinal architecture, and thus appear to be the most promising approach for maintaining close proximity between the retinal prosthetic electrodes and target neurons...
- Rlbp1 promoter drives robust Müller glial GFP expression in transgenic miceFelix R Vazquez-Chona
Department of Ophthalmology and Visual Sciences, John A Moran Eye Center, University of Utah, Salt Lake City, UT 84132, USA
Invest Ophthalmol Vis Sci 50:3996-4003. 2009..The goal of this study was to determine whether regulatory elements of the retinaldehyde binding protein 1 (Rlbp1; formerly Cralbp) gene can drive robust Müller glial gene expression in vivo...
- A computational framework for ultrastructural mapping of neural circuitryJames R Anderson
Department Ophthalmology, Moran Eye Center, University of Utah, Salt Lake City, USA
PLoS Biol 7:e1000074. 2009..Finally, this framework provides a mechanism for parallelization of ssTEM imaging, volume assembly, and data analysis across an international user base, enhancing the productivity of a large cohort of electron microscopists...
- Detection of neuron membranes in electron microscopy images using a serial neural network architectureElizabeth Jurrus
Scientific Computing and Imaging Institute, Salt Lake City, UT 84112, United States
Med Image Anal 14:770-83. 2010..We also demonstrate advantages over previous membrane detection methods. The results are a significant step towards an automated system for the reconstruction of the connectome...
- Building retinal connectomesRobert E Marc
University of Utah School of Medicine, Department of Ophthalmology John A Moran Eye Center, 65 Mario Capecchi Dr, University of Utah, Salt Lake City, UT 84132, United States
Curr Opin Neurobiol 22:568-74. 2012..The first forays into retinal connectomics have shown that even nominally well-studied cells have much richer connection graphs than expected...
- Rapid glutamate receptor 2 trafficking during retinal degenerationYanhua Lin
Department of Ophthalmology, John A, Moran Eye Center, University of Utah School of Medicine, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA
Mol Neurodegener 7:7. 2012..However, the molecular events associated with retinal remodeling remain largely unknown...
- Dysmorphic photoreceptors in a P23H mutant rhodopsin model of retinitis pigmentosa are metabolically active and capable of regenerating to reverse retinal degenerationDamian C Lee
Department of Ophthalmology and Visual Sciences and Centre for Macular Research, University of British Columbia, Vancouver, British Columbia, Canada, V5Z 3N9
J Neurosci 32:2121-8. 2012..These dystrophic photoreceptors remain metabolically active despite having lost most of their outer segments...
- Generation of an inbred miniature pig model of retinitis pigmentosaJason W Ross
Department of Animal Science, Iowa State University, Ames, Iowa, USA
Invest Ophthalmol Vis Sci 53:501-7. 2012..The objective of this investigation was to establish a transgenic miniature swine model of RP using the human P23H RHO gene...
- Automatic mosaicking and volume assembly for high-throughput serial-section transmission electron microscopyTolga Tasdizen
Electrical and Computer Engineering Department, University of Utah, Utah, USA
J Neurosci Methods 193:132-44. 2010..We also quantify the accuracy of the algorithm through a simulated image capture experiment. The publicly available software tools include the algorithms and a Graphical User Interface for easy access to the algorithms...
- Retinoid receptors trigger neuritogenesis in retinal degenerationsYanhua Lin
Department of Ophthalmology, John A Moran Eye Center, University of Utah, Salt Lake City, UT, USA
FASEB J 26:81-92. 2012..Thus, RXRs are in the final common path and may be therapeutic targets to attenuate retinal remodeling and facilitate global intervention methods in blinding diseases and other neurodegenerative disorders.
- Retinal remodeling in the Tg P347L rabbit, a large-eye model of retinal degenerationB W Jones
Department of Ophthalmology, Moran Eye Center, University of Utah, Salt Lake City, Utah 84132, USA
J Comp Neurol 519:2713-33. 2011..The relatively fast disease progression makes the TgP347L rabbit an excellent model for gene therapy, cell biological intervention, progenitor cell transplantation, surgical interventions, and bionic prosthetic studies...
- Exploring the retinal connectomeJames R Anderson
Department of Ophthalmology, Moran Eye Center, University of Utah, Salt Lake City, UT, USA
Mol Vis 17:355-79. 2011..Our goal was to produce a connectome data set for the inner plexiform layer of the mammalian retina. This paper describes our first retinal connectome, validates the method, and provides key initial findings...
- Proliferative reactive gliosis is compatible with glial metabolic support and neuronal functionFelix R Vazquez-Chona
Department of Ophthalmology and Visual Sciences, John A Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA
BMC Neurosci 12:98. 2011....