Primary open-angle glaucoma (POAG) is a leading causes of blindness and identification of a gene for this condition would have profound implications. POAG results from impaired aqueous humor outflow in the eye. Trabecular meshwork proteoglycans are the most likely candidates for regulating the outflow resistance of the aqueous humor and, thus, are one of the determinants of intraocular pressure. Identification of these proteoglycans is important in understanding the nature and mechanism of the regulation of aqueous outflow. This proposal seeks to complete our identification and characterization of trabecular proteoglycans. This work will be facilitated by the availability of new proteoglycan sequences allowing production of specific core protein peptide antibodies and oligonucleotides. A trabecular meshwork cDNA expression library will be screened by peptide antibodies and/or by degenerate oligonucleotides made against the unique trabecular meshwork proteoglycan sequences identified by us. We will localize each of these proteoglycans in the trabecular meshwork using immunohistochemistry. These complementary approaches will allow the identification of the important trabecular meshwork proteoglycans. Based on several independent lines of evidence that suggest a fundamental role of proteoglycans in regulating the aqueous outflow through the trabecular meshwork, we propose that these proteoglycans are ideal candidate genes for glaucoma. POAG families with a clear pattern of autosomal dominant inheritance will be part of a study utilizing single stranded conformation analysis or denaturing gradient gels to determine if a specific proteoglycan may be the genetic defect in one or more of these families. It is our view that POAG is a heterogeneous group of disorders, so that each of these families may actually represent a defect in a different proteoglycan or extracellular matrix component. The ultimate goal of this grant proposal is to identify one or more POAG genes. This may, in turn, lead to earlier detection and new therapeutic approaches to this insidious cause of human blindness.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY010555-01
Application #
2164494
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1994-04-01
Project End
1997-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Keller, Kate E; Yang, Yong-Feng; Sun, Ying Ying et al. (2014) Interleukin-20 receptor expression in the trabecular meshwork and its implication in glaucoma. J Ocul Pharmacol Ther 30:267-76
Pasutto, Francesca; Keller, Kate E; Weisschuh, Nicole et al. (2012) Variants in ASB10 are associated with open-angle glaucoma. Hum Mol Genet 21:1336-49
Charlesworth, Jac; Kramer, Patricia L; Dyer, Tom et al. (2010) The path to open-angle glaucoma gene discovery: endophenotypic status of intraocular pressure, cup-to-disc ratio, and central corneal thickness. Invest Ophthalmol Vis Sci 51:3509-14
Wirtz, Mary K; Samples, John R; Toumanidou, Victoria et al. (2010) Association of POAG risk factors and the Thr377Met MYOC mutation in an isolated Greek population. Invest Ophthalmol Vis Sci 51:3055-60
Wirtz, Mary K; Konstas, Anastasios G P; Samples, John R et al. (2008) Myocilin variations and familial glaucoma in Taxiarchis, a small Greek village. Mol Vis 14:774-81
Wirtz, Mary K; Samples, John R; Xu, Hong et al. (2002) Expression profile and genome location of cDNA clones from an infant human trabecular meshwork cell library. Invest Ophthalmol Vis Sci 43:3698-704
Xu, H; Acott, T S; Wirtz, M K (2000) Identification and expression of a novel type I procollagen C-proteinase enhancer protein gene from the glaucoma candidate region on 3q21-q24. Genomics 66:264-73
Wirtz, M K; Samples, J R; Rust, K et al. (1999) GLC1F, a new primary open-angle glaucoma locus, maps to 7q35-q36. Arch Ophthalmol 117:237-41
Wirtz, M K; Xu, H; Rust, K et al. (1998) Insulin-like growth factor binding protein-5 expression by human trabecular meshwork. Invest Ophthalmol Vis Sci 39:45-53
Wirtz, M K; Samples, J R; Kramer, P L et al. (1997) Mapping a gene for adult-onset primary open-angle glaucoma to chromosome 3q. Am J Hum Genet 60:296-304

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