CADHERIN DYNAMICS AND GLAUCOMA

Summary

Principal Investigator: W Daniel Stamer
Affiliation: University of Arizona
Country: USA
Abstract: Recent clinical trials demonstrate that significant, sustained intraocular pressure reduction in people with glaucoma slows or halts vision loss, even in patients with low-tension glaucoma. While the site of increased resistance in glaucoma is likely located in the conventional drainage pathway, the cellular mechanisms responsible for generation of this extra resistance are unknown. Previous work points to two possibilities that are not mutually exclusive: (i) abnormal accumulation and/or alterations in the extracellular matrix materials of the juxtacanalicular tissue;or (ii) alterations in the function of the intercellular junctions (and associated border pores) of the inner wall of Schlemm's canal. In the present application, we propose to study a family of cell-cell adhesion molecules, the cadherins, in the endothelial cells of Schlemm's canal. Cadherins form adherens junctional complexes, which are present in the conventional drainage pathway, but have only been described morphologically. Since homophilic protein- protein interactions of cadherin extracellular domains on adjacent cells are critical to the formation and maintenance of the integrity of at least three intercellular junctional complexes (including adherens, occludens and gap), and published evidence suggests that cell-cell adhesion plays a role in determining outflow resistance, we hypothesize that cadherins between Schlemm's canal endothelia strongly influence the generation of outflow resistance. Our study will examine cadherins at the molecular and functional levels and (i) specifically target cadherin-5 (plus associated catenin proteins) and disrupt adhesion between Schlemm's canal endothelia;(ii)analyze effects of pressure differences/stretch on relative expression levels, subcellular distribution and phosphorylation status of cadherin-5 plus associated catenins;and (iii) monitor signaling proteins that regulate the formation and remodeling of the cadherin-5 junction complex. Results obtained from these investigations will provide a basic understanding of the role of cadherin proteins in aqueous outflow resistance and uncover novel therapeutic targets for glaucoma therapy.
Funding Period: 2006-02-02 - 2011-01-31
more information: NIH RePORT

Top Publications

  1. pmc Pharmacologic manipulation of conventional outflow facility in ex vivo mouse eyes
    Alexandra Boussommier-Calleja
    Department of Bioengineering, Imperial College London, London, UK
    Invest Ophthalmol Vis Sci 53:5838-45. 2012
  2. pmc Outflow physiology of the mouse eye: pressure dependence and washout
    Yuan Lei
    Department of Bioengineering, Imperial College London, London, United Kingdom
    Invest Ophthalmol Vis Sci 52:1865-71. 2011
  3. pmc Structural basement membrane components and corresponding integrins in Schlemm's canal endothelia
    Saumya S VanderWyst
    Biomedical Engineering Graduate Inter Disciplinary Program, University of Arizona, Tucson, AZ 85719, USA
    Mol Vis 17:199-209. 2011
  4. pmc Mechanisms of ATP release by human trabecular meshwork cells, the enabling step in purinergic regulation of aqueous humor outflow
    Ang Li
    Department of Physiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 6085, USA
    J Cell Physiol 227:172-82. 2012
  5. pmc Cytoskeletal dependence of adenosine triphosphate release by human trabecular meshwork cells
    Ang Li
    Department of Physiology, Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6085, USA
    Invest Ophthalmol Vis Sci 52:7996-8005. 2011
  6. pmc eNOS, a pressure-dependent regulator of intraocular pressure
    W Daniel Stamer
    Department of Ophthalmology and Vision Science, University of Arizona, Tucson, Arizona, USA
    Invest Ophthalmol Vis Sci 52:9438-44. 2011
  7. pmc Mechanical responsiveness of the endothelial cell of Schlemm's canal: scope, variability and its potential role in controlling aqueous humour outflow
    E H Zhou
    Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA
    J R Soc Interface 9:1144-55. 2012
  8. pmc Protein markers and differentiation in culture for Schlemm's canal endothelial cells
    K M Perkumas
    Department of Ophthalmology and Vision Science, The University of Arizona, Tucson, Arizona, USA
    Exp Eye Res 96:82-7. 2012
  9. pmc Current understanding of conventional outflow dysfunction in glaucoma
    W Daniel Stamer
    Department of Ophthalmology, Duke University, Durham, North Carolina 27710, USA
    Curr Opin Ophthalmol 23:135-43. 2012
  10. pmc A model of giant vacuole dynamics in human Schlemm's canal endothelial cells
    Ryan M Pedrigi
    Department of Bioengineering, Imperial College London, London SW7 2AZ, UK
    Exp Eye Res 92:57-66. 2011

Scientific Experts

  • W Daniel Stamer
  • E H Zhou
  • Darryl R Overby
  • Renata F Ramos
  • Ang Li
  • Yuan Lei
  • C Ross Ethier
  • Alexandra Boussommier-Calleja
  • Grant M Sumida
  • W Daniel Stamer
  • K M Perkumas
  • Kim Peterson-Yantorno
  • Mortimer M Civan
  • Chi Ting Leung
  • Saumya S VanderWyst
  • Ryan M Pedrigi
  • A Thomas Read
  • David F Woodward
  • Jacques Bertrand
  • Claire H Mitchell
  • David Simon
  • Ashley Reed
  • Kristin M Perkumas
  • D W H Chan
  • Marlys H Witte
  • James B Hoying

Detail Information

Publications20

  1. pmc Pharmacologic manipulation of conventional outflow facility in ex vivo mouse eyes
    Alexandra Boussommier-Calleja
    Department of Bioengineering, Imperial College London, London, UK
    Invest Ophthalmol Vis Sci 53:5838-45. 2012
    ..Our goal was to determine whether pharmacologic compounds that affect conventional outflow facility in human eyes exert similar effects in C57BL/6 mice...
  2. pmc Outflow physiology of the mouse eye: pressure dependence and washout
    Yuan Lei
    Department of Bioengineering, Imperial College London, London, United Kingdom
    Invest Ophthalmol Vis Sci 52:1865-71. 2011
    ..To facilitate future use of the mouse as a model of aqueous humor outflow, several fundamental physiological parameters were measured in the mouse eye...
  3. pmc Structural basement membrane components and corresponding integrins in Schlemm's canal endothelia
    Saumya S VanderWyst
    Biomedical Engineering Graduate Inter Disciplinary Program, University of Arizona, Tucson, AZ 85719, USA
    Mol Vis 17:199-209. 2011
    ..The goal of this study was to examine integrin-extracellular matrix binding partners of the inner wall basement membrane that facilitate attachment...
  4. pmc Mechanisms of ATP release by human trabecular meshwork cells, the enabling step in purinergic regulation of aqueous humor outflow
    Ang Li
    Department of Physiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 6085, USA
    J Cell Physiol 227:172-82. 2012
    ..The P2RX(7) -dependent component of swelling-activated release may be mediated by PX1 hemichannels or reflect apoptotic magnification of ATP release, either through itself and/or hemichannels...
  5. pmc Cytoskeletal dependence of adenosine triphosphate release by human trabecular meshwork cells
    Ang Li
    Department of Physiology, Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6085, USA
    Invest Ophthalmol Vis Sci 52:7996-8005. 2011
    ..To test whether adenosine triphosphate (ATP) release links cytoskeletal remodeling with release of matrix metalloproteinases (MMPs), regulators of outflow facility and intraocular pressure...
  6. pmc eNOS, a pressure-dependent regulator of intraocular pressure
    W Daniel Stamer
    Department of Ophthalmology and Vision Science, University of Arizona, Tucson, Arizona, USA
    Invest Ophthalmol Vis Sci 52:9438-44. 2011
    ..To better understand one possible underlying molecular factor that regulates IOP, nitric oxide (NO), pressure-dependent drainage in transgenic mice overexpressing endothelial NO synthase (eNOS) was studied...
  7. pmc Mechanical responsiveness of the endothelial cell of Schlemm's canal: scope, variability and its potential role in controlling aqueous humour outflow
    E H Zhou
    Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA
    J R Soc Interface 9:1144-55. 2012
    ..Although the mechanism and locus of increased outflow resistance remain unclear, these data suggest the SC endothelial cell to be a modulator of outflow resistance...
  8. pmc Protein markers and differentiation in culture for Schlemm's canal endothelial cells
    K M Perkumas
    Department of Ophthalmology and Vision Science, The University of Arizona, Tucson, Arizona, USA
    Exp Eye Res 96:82-7. 2012
    ..One of these responsibilities, maintenance of the blood-aqueous barrier, can be modeled in culture upon withdrawal of growth factors from SC cell monolayers...
  9. pmc Current understanding of conventional outflow dysfunction in glaucoma
    W Daniel Stamer
    Department of Ophthalmology, Duke University, Durham, North Carolina 27710, USA
    Curr Opin Ophthalmol 23:135-43. 2012
    ..In the context of established knowledge, this review summarizes recent investigations of conventional outflow function, with the goal of identifying areas for future inquiry and therapeutic targeting...
  10. pmc A model of giant vacuole dynamics in human Schlemm's canal endothelial cells
    Ryan M Pedrigi
    Department of Bioengineering, Imperial College London, London SW7 2AZ, UK
    Exp Eye Res 92:57-66. 2011
    ..This model offers promising opportunities to investigate the role of endothelial cell biomechanics in the regulation of intraocular pressure in normal and glaucomatous eyes...
  11. pmc Sphingosine-1-phosphate enhancement of cortical actomyosin organization in cultured human Schlemm's canal endothelial cell monolayers
    Grant M Sumida
    Physiological Sciences Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ 85711, USA
    Invest Ophthalmol Vis Sci 51:6633-8. 2010
    ..Because of S1P's known effect of increasing barrier function in endothelial cells, the authors hypothesized that Schlemm's canal (SC) cells in culture respond to S1P by increasing actomyosin organization at the cell cortex...
  12. pmc A new method for selection of angular aqueous plexus cells from porcine eyes: a model for Schlemm's canal endothelium
    Yuan Lei
    Department of Bioengineering, Imperial College London, London, United Kingdom
    Invest Ophthalmol Vis Sci 51:5744-50. 2010
    ..The authors sought to develop a technique for isolating and culturing angular aqueous plexus (AAP) cells from more plentiful porcine eyes. AAP is an analogue of Schlemm's canal...
  13. pmc Cellular basis for bimatoprost effects on human conventional outflow
    W Daniel Stamer
    Department of Ophthalmology and Vision Science, The University of Arizona, Tucson, Arizona 85711, USA
    Invest Ophthalmol Vis Sci 51:5176-81. 2010
    ..The present study specifically examines bimatoprost effects on the cells that populate human outflow tissues...
  14. ncbi Schlemm's canal endothelia, lymphatic, or blood vasculature?
    Renata F Ramos
    Biomedical Engineering Program, The University of Arizona, Tucson, AZ, USA
    J Glaucoma 16:391-405. 2007
    ..Our evaluation concludes that the inner wall of Schlemm's canal is unique, sharing extraordinary characteristics with both types of specialized endothelia in addition to having distinctive features of its own...
  15. pmc Effects of cyclic intraocular pressure on conventional outflow facility
    Renata F Ramos
    Biomedical Engineering Graduate Program, University of Arizona, Tucson, AZ 85711, USA
    Invest Ophthalmol Vis Sci 49:275-81. 2008
    ..The purpose of the present study was to determine the effect(s) of ocular pulse on conventional outflow facility in perfused anterior segments...
  16. pmc Aquaporin-1 expression and conventional aqueous outflow in human eyes
    W Daniel Stamer
    Department of Ophthalmology and Vision Science, The University of Arizona, Tucson, AZ 85711, USA
    Exp Eye Res 87:349-55. 2008
    ..2+/-11.2%. Taken together, these results indicate that a transcellular pathway, mediated by aquaporin-1, does not contribute significantly to bulk outflow through the conventional aqueous outflow tract of human eyes...
  17. pmc The changing paradigm of outflow resistance generation: towards synergistic models of the JCT and inner wall endothelium
    Darryl R Overby
    Tulane University, Department of Biomedical Engineering, New Orleans, LA, USA
    Exp Eye Res 88:656-70. 2009
    ..Further study is greatly needed to better characterize these important interactions...
  18. pmc Cyclic mechanical stress and trabecular meshwork cell contractility
    Renata F Ramos
    Biomedical Engineering Graduate Program, University of Arizona, Tucson, AZ 85711, USA
    Invest Ophthalmol Vis Sci 50:3826-32. 2009
    ..The purpose of the present study was to examine responses of trabecular meshwork (TM) cells to cyclic biomechanical stress in the presence and absence of compounds known to affect cell contractility...
  19. pmc Sphingosine-1-phosphate effects on the inner wall of Schlemm's canal and outflow facility in perfused human eyes
    W Daniel Stamer
    Department of Ophthalmology and Vision Science, The University of Arizona, 655 North Alvernon Way, Suite 108, Tucson, AZ 85711, USA
    Exp Eye Res 89:980-8. 2009
    ..Regardless, S1P receptor antagonists represent novel therapeutic prospects for ocular hypertension in humans...
  20. pmc Targeted gene transfer to Schlemm's canal by retroperfusion
    W Daniel Stamer
    Department of Ophthalmology, The University of Arizona, Tucson, AZ, USA
    Exp Eye Res 84:843-9. 2007
    ....