Prevention of Retinal Degeneration by Crystallins in Experimental Uveitis

Summary

Principal Investigator: Narsing Rao
Affiliation: University of Southern California
Country: USA
Abstract: DESCRIPTION (provided by principal investigator): Intraocular inflammation, commonly referred to as uveitis, is a leading cause of blindness from retinal photoreceptor cell apoptosis. A robust animal model of uveitis that closely resembles human uveitis is experimental autoimmune uveoretinitis (EAU). It is characterized by two phases: the early phase, 5-7 days postimmunization (p.i.) with an uveitogenic antigen, and the late/amplification phase, 12-14 days p.i. During the late phase, macrophages/neutrophils infiltrate the retina, and photoreceptor damage is noted histologically. The early phase, preceding the leukocyte infiltration, reveals Th1- and Th17-driven cytokines in the retina, nitration of cytochrome c (cyto c) in the photoreceptors from mitochondrial oxidative stress, and the release of nitrated cyto c into the cytosol. Such cyto c release is known to cause apoptosis. However, apoptosis is not a feature of early EAU, suggesting the presence of a protective mechanism(s) in the EAU retina that prevents photoreceptor apoptosis. Current preliminary studies suggest that the protection is offered by 1A crystallin upregulation and that this is unique to the photoreceptors and are not mediated by well-recognized anti-apoptotic proteins, including 1B crystallin, heat shock protein 27 and other heat shock proteins. Significantly, 1A crystallin knockout mice with early EAU show prominent apoptosis in the retina;such apoptosis is totally absent in the wild type mice with EAU. The data reveal the significance of 1A crystallin in preventing apoptosis in the retina. Moreover, it indicates that unlike other tissues, the photoreceptors utilize 1A crystallins selectively in the prevention of oxidative stress-mediated damage in early EAU, a novel protective mechanism observed in the photoreceptors. Based on our preliminary studies we hypothesize that 1) upregulation of 1A crystallin is a feature of the photoreceptors in response to mitochondrial oxidative stress;2) upregulated 1A crystallin interacts with the oxidative stress-induced nitrated cyto c, blocking the activation of caspases, and preventing apoptosis of photoreceptors. These hypotheses will be tested by three specific aims: 1) Determine the immune mechanism of 1A crystallin upregulation in the retina during EAU;2) Determine prevention of photoreceptor apoptosis by 1A crystallin in EAU and 3) Determine photoreceptor oxidative stress induction by iNOS in EAU. In-depth analysis of the immune mechanism(s) of 1A crystallin upregulation in EAU and its protective anti- apoptotic function will enhance our understanding, by clarifying the importance of crystallin upregulation in photoreceptor protection not only in uveitis, but in other oxidative stress-mediated retinal degenerations as well. Moreover the current proposal suggests that 1A crystallin can be a promising therapeutic agent for preventing oxidative stress-mediated photoreceptor damage. Such oxidative damage has been implicated in various blinding diseases, including age-related macular degeneration, retinal vein occlusion, and glaucoma. PUBLIC HEALTH RELEVANCE AlphaA crystallin is a unique protein present in the eye and other tissues. Lack of this protein can cause blindness, and supplement of this protein can prevent several blinding diseases.
Funding Period: ----------------2008 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. pmc Phenotype of transgenic mice overexpressed with inducible nitric oxide synthase in the retina
    Guey Shuang Wu
    Department of Ophthalmology, Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
    PLoS ONE 7:e43089. 2012
  2. doi Mitochondrial oxidative stress initiates visual loss in sympathetic ophthalmia
    Yutaka Kaneko
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
    Jpn J Ophthalmol 56:191-7. 2012
  3. pmc Neuroglobin protection in retinal ischemia
    Anita S Y Chan
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
    Invest Ophthalmol Vis Sci 53:704-11. 2012
  4. doi Expression of α-crystallin in the retina of human sympathetic ophthalmia
    Satoru Kase
    Department of Ophthalmology, Laboratory of Ocular Cell Biology and Visual Science, Hokkaido University Graduate School of Medicine, Sapporo 060 8638, Japan
    Mol Med Rep 5:395-9. 2012
  5. pmc Posttranslational modification of differentially expressed mitochondrial proteins in the retina during early experimental autoimmune uveitis
    Sindhu Saraswathy
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
    Mol Vis 17:1814-21. 2011
  6. pmc The role of TLR4 activation in photoreceptor mitochondrial oxidative stress
    MinHee K Ko
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
    Invest Ophthalmol Vis Sci 52:5824-35. 2011
  7. pmc The role of TLR4 in photoreceptor {alpha}a crystallin upregulation during early experimental autoimmune uveitis
    Sindhu Saraswathy
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
    Invest Ophthalmol Vis Sci 51:3680-6. 2010
  8. pmc Expression of alpha-crystallins in human sebaceous carcinoma of the eyelid
    Panayota K Rigas
    Doheny Eye Institute, Los Angeles, California 90033, USA
    Eur J Ophthalmol 19:702-7. 2009
  9. pmc Experimental ocular tuberculosis in guinea pigs
    Narsing A Rao
    Doheny Eye Institute and Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
    Arch Ophthalmol 127:1162-6. 2009
  10. pmc Mitochondrial proteomics in experimental autoimmune uveitis oxidative stress
    Sindhu Saraswathy
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA
    Invest Ophthalmol Vis Sci 50:5559-66. 2009

Scientific Experts

  • N A Rao
  • Satoru Kase
  • Sindhu Saraswathy
  • Yutaka Kaneko
  • Guey Shuang Wu
  • Anita S Y Chan
  • MinHee K Ko
  • Panayota K Rigas
  • Meisheng Jiang
  • Matus Rehak
  • Yoshiko Nagaoka
  • Yi Hsin Liu
  • Mari Ueki
  • Jignesh G Parikh
  • Angeline M Nguyen

Detail Information

Publications11

  1. pmc Phenotype of transgenic mice overexpressed with inducible nitric oxide synthase in the retina
    Guey Shuang Wu
    Department of Ophthalmology, Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
    PLoS ONE 7:e43089. 2012
    ..In this study, we constructed transgenic mice overexpressing iNOS in the retina to evaluate the effect of sustained, intense iNOS generation in the photoreceptor damage...
  2. doi Mitochondrial oxidative stress initiates visual loss in sympathetic ophthalmia
    Yutaka Kaneko
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
    Jpn J Ophthalmol 56:191-7. 2012
    ..Such damage was associated with TNF-α, TNF-α receptors, and iNOS expression in the photoreceptors, suggesting that this molecular mechanism without retinal inflammatory cell infiltration may initiate photoreceptor damage in SO...
  3. pmc Neuroglobin protection in retinal ischemia
    Anita S Y Chan
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
    Invest Ophthalmol Vis Sci 53:704-11. 2012
    ..To explore the role of Ngb in retinal neuroprotection during ischemia reperfusion (IR), the authors examined the effect of Ngb overexpression in the retina in vivo by using Ngb-transgenic (Ngb-Tg) mice...
  4. doi Expression of α-crystallin in the retina of human sympathetic ophthalmia
    Satoru Kase
    Department of Ophthalmology, Laboratory of Ocular Cell Biology and Visual Science, Hokkaido University Graduate School of Medicine, Sapporo 060 8638, Japan
    Mol Med Rep 5:395-9. 2012
    ..This may play a protective role in the suppression of photoreceptor apoptosis associated with intraocular inflammation...
  5. pmc Posttranslational modification of differentially expressed mitochondrial proteins in the retina during early experimental autoimmune uveitis
    Sindhu Saraswathy
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
    Mol Vis 17:1814-21. 2011
    ....
  6. pmc The role of TLR4 activation in photoreceptor mitochondrial oxidative stress
    MinHee K Ko
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
    Invest Ophthalmol Vis Sci 52:5824-35. 2011
    ..Herein the authors investigated whether the activation of Toll-like receptors (TLRs) in the innate immune response causes retinal photoreceptor oxidative stress and mitochondrial DNA (mtDNA) damage...
  7. pmc The role of TLR4 in photoreceptor {alpha}a crystallin upregulation during early experimental autoimmune uveitis
    Sindhu Saraswathy
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
    Invest Ophthalmol Vis Sci 51:3680-6. 2010
    ..Such crystallin upregulation may prevent oxidative stress-mediated apoptosis of photoreceptors in uveitis...
  8. pmc Expression of alpha-crystallins in human sebaceous carcinoma of the eyelid
    Panayota K Rigas
    Doheny Eye Institute, Los Angeles, California 90033, USA
    Eur J Ophthalmol 19:702-7. 2009
    ..Crystallins are molecular chaperones that protect various cells from apoptosis. This study used immunohistochemistry to examine the expression of alphaA-crystallin and alphaB-crystallin in human sebaceous carcinoma tissues...
  9. pmc Experimental ocular tuberculosis in guinea pigs
    Narsing A Rao
    Doheny Eye Institute and Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
    Arch Ophthalmol 127:1162-6. 2009
    ..To develop an animal model of intraocular tuberculosis (TB) with features of pulmonary TB and extrapulmonary dissemination to the eye...
  10. pmc Mitochondrial proteomics in experimental autoimmune uveitis oxidative stress
    Sindhu Saraswathy
    Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA
    Invest Ophthalmol Vis Sci 50:5559-66. 2009
    ..In this study, the authors determined alterations in retinal mitochondrial protein levels in response to oxidative stress during the early phase of experimental autoimmune uveitis (EAU)...
  11. pmc Expression of heat shock protein 27 and alpha-crystallins in human retinoblastoma after chemoreduction
    S Kase
    Doheny Eye Institute, 1450 San Pablo Street, DRVC 211, Los Angeles, CA 90033, USA
    Br J Ophthalmol 93:541-4. 2009
    ..Small heat shock proteins (sHSP) play an important role in the resistance to anticancer drugs. We examined the expression of the sHSP family, HSP27 and alpha-crystallins, in human retinoblastoma with and without preoperative chemotherapy...