The Role of Outer Retinal Injury in Glaucoma

Summary

Principal Investigator: T Nork
Abstract: Despite advances in therapy, glaucoma remains one of the leading causes of blindness. In this disease, chronically elevated intraocular pressure (IOP) is a risk factor for optic nerve damage, which has traditionally been thought to occur either by mechanical damage to the retinal ganglion cell (RGC) axons, or by reduced blood flow to the nerve. However, the Principal Investigator and colleagues have recently reported morphologic evidence for injury to the cone photoreceptors in both humans with a diagnosis of glaucoma and in an experimental model of chronic glaucoma. This group has also found evidence for injury at the molecular level. Specifically, that there is decreased production of opsin-specific messenger RNA in the L/M- cones (long and medium wavelength-sensitive) in both experimental glaucoma as well as human glaucoma. Preliminary electrophysiological data also suggest partial functional impairment of the cones, which appears to be most prominent in the arcuate (mid-peripheral) region that is known to be affected earliest in human chronic glaucoma. Based on these findings, an alternative hypothesis is proposed for a mechanism that might contribute to RGC death in glaucoma. Namely, that elevated IOP results in decreased choroidal blood flow causing ischemic injury to the photoreceptors. This is followed by transmission of the damaging effects (perhaps involving elevated levels of glutamate due to decreased re-uptake or transport) in an anterograde direction to the inner retina, leading to or exacerbating RGC injury. The aim of this proposal is to test specific predictions of this anterograde hypothesis relating to alterations in choroidal blood flow and the functional sequence of events that occur in a model of experimental glaucoma. Experiments include: measurement of choroidal blood flow using a microsphere impaction technique, in situ hybridization and mRNAse protection assay with opsin specific probes, and multifocal as well as full-field electroretinography.
Funding Period: 2002-04-01 - 2006-03-31
more information: NIH RePORT

Top Publications

  1. pmc Structural and functional effects of hemiretinal endodiathermy axotomy in cynomolgus macaques
    Ryan J Dashek
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792 3220, USA
    Invest Ophthalmol Vis Sci 54:3479-92. 2013
  2. pmc Structure/function studies and the effects of memantine in monkeys with experimental glaucoma
    B Ann T Gabelt
    Department of Ophthalmology and Visual Sciences, University of Wisconsin Madison, Madison, Wisconsin 53705, USA
    Invest Ophthalmol Vis Sci 53:2368-76. 2012
  3. pmc The effect of pentobarbital sodium and propofol anesthesia on multifocal electroretinograms in rhesus macaques
    Charlene B Y Kim
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
    Doc Ophthalmol 124:59-72. 2012
  4. pmc Serial multifocal electroretinograms during long-term elevation and reduction of intraocular pressure in non-human primates
    T Michael Nork
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave F4 336, Madison, WI 53792 3220, USA
    Doc Ophthalmol 120:273-89. 2010
  5. ncbi Comparison of the distribution of glial fibrillary acidic protein, heat shock protein 60, and hypoxia-inducible factor-1alpha in retinas from glaucomatous and normal canine eyes
    Caitlin A Savagian
    Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53792 3220, USA
    Am J Vet Res 69:265-72. 2008
  6. ncbi Decrease of cone opsin mRNA in experimental ocular hypertension
    Heather R Pelzel
    Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53704, USA
    Mol Vis 12:1272-82. 2006
  7. ncbi Measurement of regional choroidal blood flow in rabbits and monkeys using fluorescent microspheres
    T Michael Nork
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison 53792 3220, USA
    Arch Ophthalmol 124:860-8. 2006
  8. ncbi Effect of H-7 and Lat-B on retinal physiology
    J A Kiland
    Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, WI 53792, USA
    Curr Eye Res 31:441-55. 2006
  9. ncbi Effects of reference electrode location on monopolar-derived multifocal electroretinograms in cynomolgus monkeys
    Charlene B Y Kim
    Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, WI 53792 3220, USA
    Doc Ophthalmol 111:113-25. 2005
  10. ncbi Sympathetic ophthalmia following evisceration: a rare case
    Gregory J Griepentrog
    Department of Ophthalmology and Visual Sciences, University of Wisconsin Madison, Madison, Wisconsin 53792, USA
    Ophthal Plast Reconstr Surg 21:316-8. 2005

Scientific Experts

  • Charlene B Y Kim
  • T Nork
  • J A Kiland
  • Ryan J Dashek
  • James N Ver Hoeve
  • Carol A Rasmussen
  • B Ann T Gabelt
  • Caitlin A Savagian
  • Heather R Pelzel
  • Gregory J Griepentrog
  • Elizabeth A Hennes-Beean
  • Paul L Kaufman
  • Ozan Y Tektas
  • John C Peterson
  • Elke L├╝tjen-Drecoll
  • Richard R Dubielzig
  • Robert W Nickells
  • James A Ver Hoeve
  • Gretchen L Poulsen
  • Cassandra L Schlamp
  • Mark J Lucarelli
  • Daniel M Albert

Detail Information

Publications10

  1. pmc Structural and functional effects of hemiretinal endodiathermy axotomy in cynomolgus macaques
    Ryan J Dashek
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792 3220, USA
    Invest Ophthalmol Vis Sci 54:3479-92. 2013
    ..Outer retinal injury has been well described in glaucoma. To better understand the source of this injury, we wanted to develop a reliable model of partial retinal ganglion cell (RGC) axotomy...
  2. pmc Structure/function studies and the effects of memantine in monkeys with experimental glaucoma
    B Ann T Gabelt
    Department of Ophthalmology and Visual Sciences, University of Wisconsin Madison, Madison, Wisconsin 53705, USA
    Invest Ophthalmol Vis Sci 53:2368-76. 2012
    ..These structural changes may or may not lead to central functional changes as shown by the mfVEP in response to investigational therapies...
  3. pmc The effect of pentobarbital sodium and propofol anesthesia on multifocal electroretinograms in rhesus macaques
    Charlene B Y Kim
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
    Doc Ophthalmol 124:59-72. 2012
    ..Given the advantages of a stable anesthetic plane with continuous intravenous infusion and a smoother, more rapid recovery, PF is an appealing alternative for mfERG testing in rhesus macaques...
  4. pmc Serial multifocal electroretinograms during long-term elevation and reduction of intraocular pressure in non-human primates
    T Michael Nork
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave F4 336, Madison, WI 53792 3220, USA
    Doc Ophthalmol 120:273-89. 2010
    ..These results demonstrate species-specific changes in cone-driven retinal function during periods of elevated IOP. These IOP-related effects can occur in the absence of retinal ganglion cells and may be reversible...
  5. ncbi Comparison of the distribution of glial fibrillary acidic protein, heat shock protein 60, and hypoxia-inducible factor-1alpha in retinas from glaucomatous and normal canine eyes
    Caitlin A Savagian
    Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53792 3220, USA
    Am J Vet Res 69:265-72. 2008
    ..To determine the effect of acute (clinical history of glaucoma for <or= 2 days) and chronic (clinical history of glaucoma for 7 days) goniodysgenesis-related glaucoma on various stress-inducible proteins in canine retinas...
  6. ncbi Decrease of cone opsin mRNA in experimental ocular hypertension
    Heather R Pelzel
    Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53704, USA
    Mol Vis 12:1272-82. 2006
    ..As a measure of this effect, we examined the levels of rod opsin, and red/green and blue cone opsin mRNAs in monkeys with experimental ocular hypertension and glaucoma and in human eyes from donors with diagnosed glaucoma...
  7. ncbi Measurement of regional choroidal blood flow in rabbits and monkeys using fluorescent microspheres
    T Michael Nork
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison 53792 3220, USA
    Arch Ophthalmol 124:860-8. 2006
    ..To develop a quantitative measure of regional variation in choroidal blood flow (ChBF)...
  8. ncbi Effect of H-7 and Lat-B on retinal physiology
    J A Kiland
    Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, WI 53792, USA
    Curr Eye Res 31:441-55. 2006
    ..To investigate the effects of H-7 and Latrunculin B (Lat-B) on retinal vascular permeability and electrophysiology at concentrations that increase outflow facility in monkeys...
  9. ncbi Effects of reference electrode location on monopolar-derived multifocal electroretinograms in cynomolgus monkeys
    Charlene B Y Kim
    Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, WI 53792 3220, USA
    Doc Ophthalmol 111:113-25. 2005
    ..K1 and K2.1 implicit times in males were longer than in females. Quadrant groupings revealed generally larger K1 and K2.1 amplitudes in nasal than in temporal retina...
  10. ncbi Sympathetic ophthalmia following evisceration: a rare case
    Gregory J Griepentrog
    Department of Ophthalmology and Visual Sciences, University of Wisconsin Madison, Madison, Wisconsin 53792, USA
    Ophthal Plast Reconstr Surg 21:316-8. 2005
    ..We provide a brief review of sympathetic ophthalmia following evisceration and discuss the importance of a high degree of clinical suspicion and prompt treatment with high-dose systemic corticosteroids or other immunomodulators...