Glaucoma is a leading cause of blindness. Elevated intraocular pressure (IOP) is a major risk factor for glaucoma. Our goal is to identify and characterize genetic factors that contribute to elevated IOP and glaucoma. Specifically, we are using the mouse as a model system to conduct a phenotype driven mutagenesis screen to identify novel mechanisms and pathways involved in glaucoma pathogenesis. The power of phenotype driven mutagenesis screen is that there is no requisite a priori information for factors or pathways involved. Since little is currently known about IOP homeostasis, this method for identification of new genetic factors is ideal. We propose that in the time of this grant we will identify approximately 10 new glaucoma related mutations. This method has already provided us with one new locus (Eel) for primary congenital glaucoma that we propose to clone and a second enlarged eye mutant (Ee3) that we will characterize and fine map. A feature of our phenotype-driven screen is enrichment for mutation detection on mouse chromosome 5, in a region of conserved synteny to human chromosome 7q36. This region contains 2 human glaucoma loci for which the genetic cause is unknown. While we are able to enrich for this region of considerable interest, our method does not impede the likelihood of identifying mutations elsewhere in the genome. Therefore, mutations contributing to IOP and will be mapped and prioritized based on similarity to human glaucomatous phenotypes and known human glaucoma map positions. We predict that using the power of a phenotype driven mutagenesis screen in parallel with our unique tools to examine ocular phenotypes we will be able to identify and characterize new genetic factors that contribute to elevated IOP and advance understanding of glaucoma.
| Choquet, Hélène; Paylakhi, Seyyedhassan; Kneeland, Stephen C et al. (2018) A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci. Nat Commun 9:2278 |
| Williams, Pete A; Harder, Jeffrey M; John, Simon W M (2017) Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma. J Glaucoma 26:1161-1168 |
| Thomson, Benjamin R; Souma, Tomokazu; Tompson, Stuart W et al. (2017) Angiopoietin-1 is required for Schlemm's canal development in mice and humans. J Clin Invest 127:4421-4436 |
| Harder, Jeffrey M; Braine, Catherine E; Williams, Pete A et al. (2017) Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective. Proc Natl Acad Sci U S A 114:E3839-E3848 |
| Williams, Pete A; Harder, Jeffrey M; Foxworth, Nicole E et al. (2017) Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 355:756-760 |
| Williams, Pete A; Harder, Jeffrey M; Foxworth, Nicole E et al. (2017) Nicotinamide and WLDS Act Together to Prevent Neurodegeneration in Glaucoma. Front Neurosci 11:232 |
| Williams, Pete A; Braine, Catherine E; Foxworth, Nicole E et al. (2017) GlyCAM1 negatively regulates monocyte entry into the optic nerve head and contributes to radiation-based protection in glaucoma. J Neuroinflammation 14:93 |
| Nair, K Saidas; Cosma, Mihai; Raghupathy, Narayanan et al. (2016) YBR/EiJ mice: a new model of glaucoma caused by genes on chromosomes 4 and 17. Dis Model Mech 9:863-71 |
| Williams, Pete A; Tribble, James R; Pepper, Keating W et al. (2016) Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma. Mol Neurodegener 11:26 |
| Kizhatil, Krishnakumar; Chlebowski, Arthur; Tolman, Nicholas G et al. (2016) An In Vitro Perfusion System to Enhance Outflow Studies in Mouse Eyes. Invest Ophthalmol Vis Sci 57:5207-5215 |
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