In the United States, Primary Open Angle Glaucoma (POAG) is the second leading cause of blindness in the general population and the leading cause of blindness among African Americans. Due to the asymptomatic nature of the disease even at considerably advanced stages, many patients are not diagnosed with POAG until irreversible blindness has occurred. Fundamental questions about basic pathogenic mechanisms of POAG remain unanswered. Improved treatment for glaucoma patients requires better understanding of the disease mechanisms and development of early detection strategies. Our broad long term goals are to understand the disease pathophysiology and to provide tools for early detection and better treatment of this devastating disease. A genetic component for POAG is suggested by the fact that family history of the disease is one of the most important risk factors. Identification of genes contributing to POAG is of primary importance to develop improved treatment and early diagnosis strategies for POAG. Over 4 decades ago, a colony of Beagles with hereditary POAG was established, and to this day remains the only naturally occurring animal model for human POAG. Taking advantage of this well-established model, we have recently identified a small genetic interval that contains the genetic mutation causing POAG in the Beagles. The objective of this project is to identify the genetic mutation causing POAG in Beagles. To accomplish this goal, we will apply the emergent technology of Next Generation Sequencing to determine the DNA sequence of the entire region. Candidate genetic variants will be identified by comparing the sequences of affected and unaffected dogs from the POAG Beagle colony and unrelated unaffected Beagles. These genetic variants will identify candidate disease genes. Validity of the candidate genes will be tested by investigating their expression in ocular tissues from affected and unaffected Beagles. The work proposed here would promote and extend the use of the new genetic technologies of sequence capture and Next Generation Sequencing in the application of disease gene identification. Successful completion of this project would result in identification and verification of a gene causing POAG, which will likely be a major contribution to glaucoma research leading to improved treatment and early detection for glaucoma patients.

Public Health Relevance

Narrative The main objective of this proposal is to identify the gene causing primary open angle glaucoma in Beagles. Based on our preliminary results, we project that the gene will be novel and involved in aqueous humor outflow regulation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY020894-01
Application #
7947786
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Agarwal, Neeraj
Project Start
2010-09-01
Project End
2013-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
1
Fiscal Year
2010
Total Cost
$397,375
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Hazlewood, Ralph J; Chen, Qingxia; Clark, Frances K et al. (2018) Differential effects of angiotensin II type I receptor blockers on reducing intraocular pressure and TGF? signaling in the mouse retina. PLoS One 13:e0201719
Drewry, Michelle D; Challa, Pratap; Kuchtey, John G et al. (2018) Differentially expressed microRNAs in the aqueous humor of patients with exfoliation glaucoma or primary open-angle glaucoma. Hum Mol Genet 27:1263-1275
Patel, Shriji; Ling, Jeanie; Kim, Stephen J et al. (2016) Proteomic Analysis of Macular Fluid Associated With Advanced Glaucomatous Excavation. JAMA Ophthalmol 134:108-10
Nathan, Niraj; Kuchtey, Rachel W (2016) Genetics, Diagnosis, and Monitoring of Pseudoexfoliation Glaucoma. Curr Ophthalmol Rep 4:206-212
Breazzano, Mark P; Mawn, Louise A; Kuchtey, Rachel W (2016) Spontaneous Resolution of Presumed Idiopathic Elevated Episcleral Venous Pressure. J Glaucoma 25:e751-2
Kuchtey, Rachel W; Naratadam, George T; Kuchtey, John (2015) Severe open angle glaucoma in hereditary hemorrhagic telangiectasia. Clin Case Rep 3:725-7
Burgess, L Goodwin; Uppal, Karan; Walker, Douglas I et al. (2015) Metabolome-Wide Association Study of Primary Open Angle Glaucoma. Invest Ophthalmol Vis Sci 56:5020-8
Kuchtey, John; Kuchtey, Rachel W (2014) The microfibril hypothesis of glaucoma: implications for treatment of elevated intraocular pressure. J Ocul Pharmacol Ther 30:170-80
Kuchtey, John; Kunkel, Jessica; Burgess, L Goodwin et al. (2014) Elevated transforming growth factor ?1 in plasma of primary open-angle glaucoma patients. Invest Ophthalmol Vis Sci 55:5291-7
Kuchtey, John; Kunkel, Jessica; Esson, Douglas et al. (2013) Screening ADAMTS10 in dog populations supports Gly661Arg as the glaucoma-causing variant in beagles. Invest Ophthalmol Vis Sci 54:1881-6

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