A molecular component involved in the pathogenesis of open-angle glaucoma has been identified. Mutations causing ocular hypertension and open-angle glaucoma in some are located to a glaucoma gene on a chromosome 1 locus, GLC1A, that codes for a protein called myocilin. Unfortunately the function of myocilin is unknown. Myocilin is expressed by several eye tissues, including the trabecular meshwork, the likely site of pathology for ocular hypertension in open-angle glaucoma. On a subcellular level, myocilin localizes to the vesicular compartment of trabecular meshwork cells, implicating vesicular traffic and/or secretion as affected pathways in glaucoma. Progress in the initial funding period of this project characterized myocilin as a cytosolic protein that associates with a class of intracellular vesicles in trabecular meshwork cells called """"""""exosomes"""""""". Thus, myocilin is not secreted in a traditional manner, but exits trabecular meshwork cells and enters the extracellular compartment associated with exosomes. The overall goal of the present proposal is to determine the function of myocilin in trabecular meshwork cells and how mutations in myocilin impact its extracellular appearance. We hypothesize that mutations in myocilin interfere with delivery of exosomes for release. To test this hypothesis, we have designed two complimentary specific aims: (i) Identify the mechanism by which myocilin associates with intracellular membranes (exosomes) in trabecular meshwork cells and (ii) Determine effects of myocilin mutants on release of exosomes from human trabecular meshwork cells .

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Agarwal, Neeraj
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University of Arizona
Schools of Medicine
United States
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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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