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.

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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Medical College of Wisconsin
Anatomy/Cell Biology
Schools of Medicine
United States
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Huckenpahler, Alison; Wilk, Melissa; Link, Brian et al. (2018) Repeatability and Reproducibility of In Vivo Cone Density Measurements in the Adult Zebrafish Retina. Adv Exp Med Biol 1074:151-156
Lapierre-Landry, Maryse; Huckenpahler, Alison L; Link, Brian A et al. (2018) Imaging Melanin Distribution in the Zebrafish Retina Using Photothermal Optical Coherence Tomography. Transl Vis Sci Technol 7:4
Wilk, Melissa A; Huckenpahler, Alison L; Collery, Ross F et al. (2017) The Effect of Retinal Melanin on Optical Coherence Tomography Images. Transl Vis Sci Technol 6:8
Hilinski, William C; Bostrom, Jonathan R; England, Samantha J et al. (2016) Lmx1b is required for the glutamatergic fates of a subset of spinal cord neurons. Neural Dev 11:16
Huckenpahler, Alison L; Wilk, Melissa A; Cooper, Robert F et al. (2016) Imaging the adult zebrafish cone mosaic using optical coherence tomography. Vis Neurosci 33:E011
Porazinski, Sean; Wang, Huijia; Asaoka, Yoichi et al. (2015) YAP is essential for tissue tension to ensure vertebrate 3D body shape. Nature 521:217-221
Yeo, Nan Cher; O'Meara, Caitlin C; Bonomo, Jason A et al. (2015) Shroom3 contributes to the maintenance of the glomerular filtration barrier integrity. Genome Res 25:57-65
Paulus, Jeremiah D; Link, Brian A (2014) Loss of optineurin in vivo results in elevated cell death and alters axonal trafficking dynamics. PLoS One 9:e109922
Tang, Yujie; Gholamin, Sharareh; Schubert, Simone et al. (2014) Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med 20:732-40
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

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