This laboratory is appropriately titled Translational Research, as we use inherited retinal degenerations identified in the clinic as both a source of clues about retinal function and dysfunction and a target for research in therapeutic intervention. The broad direction for our laboratory involves the biology of photoreceptor rescue and repair and opportunities to initiate human clinical rescue trials for RP and allied diseases based on animal studies. We have studied a number of mouse and rat models of human retinal degeneration diseases to elucidate the mechanisms of retinal neural signaling deficiencies and degeneration leading to blindness. We use normal rodents and rodents that are genetically altered to mimic human retinal disease to study the characteristics (phenotype), molecular genetics, physiological mechanisms and possible treatments of these inherited retinal degenerations. Our laboratory applies the techniques of light and electron microscopy, immunohistochemistry, biochemistry, and molecular biology to human and animal retinal tissue, as well as the electroretinogram (ERG) and behavioral measurements to access retinal function in animals in ways similar to those used to evaluate human vision in the clinic. These studies address human conditions of retinal and macular degenerations and age-related macular degeneration. Mechanisms of Retinal Degeneration: In last years report we described our studies using antibodies to investigate retinal pathophysiology. We developed a novel method for blocking specific membrane channels, including glial potassium channels, and receptors in the retina by injecting antibodies. We used the non-invasive electroretinogram immunohistochemistry to identify the cellular target and functional consequences of antibody injection. This approach provides a powerful opportunity to probe mechanisms of disease states using antibodies and non-invasive ERG response recordings to probe pathophysiologic mechanisms in vivo, even during treatment. This year we continue a molecular approach to studying retinal disease mechanisms by investigating the role Rac1 in photoreceptor plasticity and homeostasis in normal and diseased retinas. A critical facet of retinal neurodegenerative disease involves the structural changes, particularly to the photoreceptor outer segments (OS) that precede photoreceptor death, causing loss of vision. As photoreceptor cells undergo primary degeneration through progressive outer segment (OS) shortening in many of these conditions, a critical question is whether the outer segment may exhibit sufficient structural plasticity to support elongation of OS that have been shortened by disease states and whether this would promote survival of the photoreceptor cell. The goal of the work is to investigate the molecules that are important in the regulation of OS length under light stress and genetic degenerative conditions. We are focusing on neurotrophic factors, such as CNTF, and on small molecules that regulate cytoskeletal growth, including RAC1. In addition to its role as a cytoskeletal element, RAC1 is a component of NADPH oxidase, which is known to cause oxidative damage in some tissues such as the heart. Some retinal degenerations caused by inherited and environmental factors, such as light, are thought to involve stress-induced oxidative damage. Last year we showed that mice with an estimated 50% knockdown in photoreceptor Rac1 had reduced photoreceptor death due to bright light exposure. The knockdown did not affect any other retinal function, including visual acuity, electroretinographic response and visual pigment photochemistry, or development and maintenance of retinal structure. This evidence points to Rac1 as a key component of the pathway leading to light-induced photoreceptor death through activation of NADPH oxidase. We are continuing to explore the role of Rac1 in retinal oxidative damage using other knockout and transgenic mice as well as Rac1 inhibitors. Rod And Cone Pathway Interactions In Mutant Mice Lacking Rod Function: Retinal visual function depends on rod and cone photoreceptors and associated neural pathways. We are studying the cone pathway responses in mutant mice that lack functional rods due to knockout of either of two genes: NRL, which is necessary for the development of rods, or rhodopsin, which is necessary for the development of their photoreceptive membrane and capacity to respond to light. These results show that (1) the rod pathway that develops in the absence of functional rods is physiologically intact, which could be important for a therapy that replaces the non functioning rods and (2) cones that develop in place of rods in the NRL knockout model signal through the rod pathway, which is a physiological demonstration of retinal plasticity, the ability to modify neuronal connections in response to developmental and disease changes. Retinoschisnin Function in Photoreceptors: Mutations in the gene for retinoschisin found on the X chromosome cause X-linked retinoschisis (XLRS). XLRS is an inherited disease and is a leading cause of juvenile macular degeneration in human males. Retinoschisin is found primarily on the outer membrane of photoreceptor inner segments. However, the role of retinoschisin in photoreceptor function is not known. We showed that in mice lacking retinoschesin photoreceptor morphology and electrophysiological responses are severely affected. Using the electroretinogram, confocal immunohistochemistry, rhodopsin photochemistry and western blot analysis of photoreceptor proteins we are studying how retinoshcisin deficiency affects photoreceptor function. In particular, we are interested in the movement of transduction proteins, such as transducin and arrestin, between the inner and outer segments in response to ambient illumination. This is thought to be a mechanism for light adaptation and/or photoreceptor protection from chronic light exposure. We have found that in young mice lacking retinoschisin, the light sensitivity of transducin translocation is greatly reduced, but it increases with age to almost normal levels within several weeks. We are currently investigating the reasons for this decreased sensitivity.

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National Institute on Deafness and Other Communication Disorders
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Marangoni, Dario; Yong, Zeng; Kjellström, Sten et al. (2017) Rearing Light Intensity Affects Inner Retinal Pathology in a Mouse Model of X-Linked Retinoschisis but Does Not Alter Gene Therapy Outcome. Invest Ophthalmol Vis Sci 58:1656-1664
Zeng, Yong; Petralia, Ronald S; Vijayasarathy, Camasamudram et al. (2016) Retinal Structure and Gene Therapy Outcome in Retinoschisin-Deficient Mice Assessed by Spectral-Domain Optical Coherence Tomography. Invest Ophthalmol Vis Sci 57:OCT277-87
Song, Hongman; Vijayasarathy, Camasamudram; Zeng, Yong et al. (2016) NADPH Oxidase Contributes to Photoreceptor Degeneration in Constitutively Active RAC1 Mice. Invest Ophthalmol Vis Sci 57:2864-75
Cukras, Catherine; Flamendorf, Jason; Wong, Wai T et al. (2016) LONGITUDINAL STRUCTURAL CHANGES IN LATE-ONSET RETINAL DEGENERATION. Retina 36:2348-2356
Bush, Ronald A; Zeng, Yong; Colosi, Peter et al. (2016) Preclinical Dose-Escalation Study of Intravitreal AAV-RS1 Gene Therapy in a Mouse Model of X-linked Retinoschisis: Dose-Dependent Expression and Improved Retinal Structure and Function. Hum Gene Ther 27:376-89
Veleri, Shobi; Lazar, Csilla H; Chang, Bo et al. (2015) Biology and therapy of inherited retinal degenerative disease: insights from mouse models. Dis Model Mech 8:109-29
Bush, Ronald A; Wei, Lisa L; Sieving, Paul A (2015) Convergence of Human Genetics and Animal Studies: Gene Therapy for X-Linked Retinoschisis. Cold Spring Harb Perspect Med 5:
Ou, Jingxing; Vijayasarathy, Camasamudram; Ziccardi, Lucia et al. (2015) Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer. J Clin Invest 125:2891-903
Song, Hongman; Bush, Ronald A; Vijayasarathy, Camasamudram et al. (2014) Transgenic expression of constitutively active RAC1 disrupts mouse rod morphogenesis. Invest Ophthalmol Vis Sci 55:2659-68
Ziccardi, Lucia; Vijayasarathy, Camasamudram; Bush, Ronald A et al. (2014) Photoreceptor pathology in the X-linked retinoschisis (XLRS) mouse results in delayed rod maturation and impaired light driven transducin translocation. Adv Exp Med Biol 801:559-66

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