The first molecular component involved in the pathogenesis of open-angle glaucoma has been identified. Mutations causing glaucoma in some are located to an open-angle glaucoma gene, GLC1A, on chromosome 1 that codes for a protein called myocilin. Myocilin is a novel protein of unknown function that is found in several eye tissues, including the trabecular meshwork, the likely site of pathology in open-angle glaucoma. On a subcellular level, myociin localizes to the vesicular compartment of trabecular meshwork cells, implicating vesicular traffic and/or secretion as affected pathways in open-angle glaucoma. Computer analyses of myocilin's primary sequence indicate significant homology to the SNARE [soluble N-ethylmaleimide sensitive fusion protein (NSF) attachment protein (SNAP) receptor] and Olfactomedin protein families, both of which localize to and function in the secretory pathway of cells. Moreover, preliminary data presented in this proposal indicate that 1) myocilin functions in both the formation and fusion of secretory-type vesicles in trabecular meshwork (HTM) cells and 2) myocilin-associated vesicles participate in the regulated assembly of nascent cell-cell junctions in two different epithelial cell models. Thus, the overall goal of this grant proposal is to determine the role of myocilin in the process of nascent cell-cell junction assembly in trabecular meshwork cells and the functional consequence of mutations in myocilin on this process. To this end, colocalization studies of myocilin with proteins known to participate in nascent cell-cell junctions will be performed in HTM cells. Second, the regulated targeting of myocilin to nascent cell-cell junctions in HTM cells will be studied. Finally, the functional consequence of mutations in myocilin (disease causing in humans) will be monitored using HTM cells as a model. These studies are designed to examine the molecular pathway in which myocilin functions in HTM cells. This knowledge will contribute to our understanding of glaucoma at the molecular level and provide new therapeutic targets for the treatment of those who are afflicted with glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012797-02
Application #
6518651
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
2001-07-02
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$290,125
Indirect Cost
Name
University of Arizona
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Stamer, W Daniel; Acott, Ted S (2012) Current understanding of conventional outflow dysfunction in glaucoma. Curr Opin Ophthalmol 23:135-43
Dismuke, W Michael; McKay, Brian S; Stamer, W Daniel (2012) Myocilin, a component of a membrane-associated protein complex driven by a homologous Q-SNARE domain. Biochemistry 51:3606-13
Perkumas, K M; Stamer, W D (2012) Protein markers and differentiation in culture for Schlemm's canal endothelial cells. Exp Eye Res 96:82-7
Stamer, W D; Hoffman, E A; Luther, J M et al. (2011) Protein profile of exosomes from trabecular meshwork cells. J Proteomics 74:796-804
VanderWyst, Saumya S; Perkumas, Kristin M; Read, A Thomas et al. (2011) Structural basement membrane components and corresponding integrins in Schlemm's canal endothelia. Mol Vis 17:199-209
Howell, Kyle G; Vrabel, Anne M; Chowdhury, Uttio Roy et al. (2010) Myocilin levels in primary open-angle glaucoma and pseudoexfoliation glaucoma human aqueous humor. J Glaucoma 19:569-75
Stamer, W Daniel; Piwnica, David; Jolas, Thierry et al. (2010) Cellular basis for bimatoprost effects on human conventional outflow. Invest Ophthalmol Vis Sci 51:5176-81
Hoffman, Emely A; Perkumas, Kristin M; Highstrom, Lindsey M et al. (2009) Regulation of myocilin-associated exosome release from human trabecular meshwork cells. Invest Ophthalmol Vis Sci 50:1313-8
Stamer, W Daniel; Read, A Thomas; Sumida, Grant M et al. (2009) Sphingosine-1-phosphate effects on the inner wall of Schlemm's canal and outflow facility in perfused human eyes. Exp Eye Res 89:980-8
Wan, Zhou; Woodward, David F; Cornell, Clive L et al. (2007) Bimatoprost, prostamide activity, and conventional drainage. Invest Ophthalmol Vis Sci 48:4107-15

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