The glaucomas are a group of vision impairing diseases characterized by progressive optic nerve damage, retinal ganglion cell death, and visual field loss. Risk factors include age, family history, anterior segment dysgenesis, elevated intraocular pressure, and high myopia. The complex nature and constraints of traditional genetic approaches in humans and mammalian model systems has limited the identification of most genes that impact glaucoma. We have developed methodologies and tools in zebrafish to detect and study glaucoma- associated phenotypes in both embryonic and adult zebrafish. We have also isolated mutants that display glaucoma-associated phenotypes. The bugeye mutation is an example in that mutant fish show elevated intraocular pressure, high myopia/buphthalmia, and progressive ganglion cell loss. In the current study we propose experiments to explore the signaling pathways that underlie the ocular phenotypes of bugeye mutants. In addition, we will explore the cell biological basis of the anterior segment and neuronal pathology. Finally, we will study one potential suppressor mutant that we identified through linkage analysis, while also pursuing the identification of other modifier genes of the bugeye phenotypes.

Public Health Relevance

Glaucoma is a significant health problem within the United States and world in general. Due to the complex nature of the disease, a full understanding of the genetic basis and underlying cellular and molecular mechanisms of disease pathology is lacking. In this proposal we describe studies in zebrafish, a relevant model system with many experimental advantages, to understand the genetic susceptibilities and cellular mechanisms of key phenotypes that are associated with glaucoma and that act as risk factors for the disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016060-08
Application #
8307699
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Agarwal, Neeraj
Project Start
2004-12-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$382,500
Indirect Cost
$132,500
Name
Medical College of Wisconsin
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Collery, Ross F; Veth, Kerry N; Dubis, Adam M et al. (2014) Rapid, accurate, and non-invasive measurement of zebrafish axial length and other eye dimensions using SD-OCT allows longitudinal analysis of myopia and emmetropization. PLoS One 9:e110699
Veth, Kerry N; Willer, Jason R; Collery, Ross F et al. (2011) Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma. PLoS Genet 7:e1001310
Collery, Ross F; Link, Brian A (2011) Dynamic smad-mediated BMP signaling revealed through transgenic zebrafish. Dev Dyn 240:712-22
Volkmann, Bethany A; Zinkevich, Natalya S; Mustonen, Aki et al. (2011) Potential novel mechanism for Axenfeld-Rieger syndrome: deletion of a distant region containing regulatory elements of PITX2. Invest Ophthalmol Vis Sci 52:1450-9
McMahon, Carrie; Gestri, Gaia; Wilson, Stephen W et al. (2009) Lmx1b is essential for survival of periocular mesenchymal cells and influences Fgf-mediated retinal patterning in zebrafish. Dev Biol 332:287-98
Skarie, Jonathan M; Link, Brian A (2009) FoxC1 is essential for vascular basement membrane integrity and hyaloid vessel morphogenesis. Invest Ophthalmol Vis Sci 50:5026-34
Gray, Matthew P; Smith, Richard S; Soules, Kelly A et al. (2009) The aqueous humor outflow pathway of zebrafish. Invest Ophthalmol Vis Sci 50:1515-21
Skarie, Jonathan M; Link, Brian A (2008) The primary open-angle glaucoma gene WDR36 functions in ribosomal RNA processing and interacts with the p53 stress-response pathway. Hum Mol Genet 17:2474-85
Berry, Fred B; Skarie, Jonathan M; Mirzayans, Farideh et al. (2008) FOXC1 is required for cell viability and resistance to oxidative stress in the eye through the transcriptional regulation of FOXO1A. Hum Mol Genet 17:490-505
Zinkevich, Natalya S; Bosenko, Dmitry V; Link, Brian A et al. (2006) laminin alpha 1 gene is essential for normal lens development in zebrafish. BMC Dev Biol 6:13

Showing the most recent 10 out of 13 publications