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. ncbi 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
  2. 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
  3. ncbi 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
  4. ncbi 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
  5. ncbi 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
  6. ncbi 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
  7. ncbi 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

Scientific Experts

Detail Information

Publications7

  1. ncbi 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
    ....
  2. 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...
  3. ncbi 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...
  4. ncbi 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...
  5. ncbi 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...
  6. ncbi 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...
  7. ncbi 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...