Glaucoma is a leading cause of blindness. Elevated intraocular pressure (IOP) is a major risk factor for glaucoma. Our goal is to continue to identify and characterize genetic factors that contribute to elevated IOP and glaucoma. 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 a phenotype driven screen is that there is no requisite, a priori information for factors or pathways involved. In our previous funding period, we have identified a number of glaucoma relevant mouse mutants (Grms) that show hallmarks of glaucoma including high IOP, retinal ganglion cell death and optic nerve atrophy. In this proposal, we will identify the causative mutations in a few of these glaucoma-relevant mutants that we have started to study. We will characterize the genetic pathways involved and carry out more detailed investigations into the pathogenesis. Very few mouse models of glaucoma exist and our mutants will be valuable both as models for understanding human glaucoma and for facilitating the identification of human mutations. Since the small number of available mutants severely limits mouse studies of glaucoma, we propose a new Cyp 1b1 -sensitized END screen for dominant glaucoma mutations. A number of reported human glaucoma loci have a dominant effect. Mutations in the human CYP1B1 gene predispose people to high IOP and glaucoma, a predisposition we have repeated in mice. We will screen 1000 G1 males/year for IOP elevation and other ocular abnormalities, ten times more families than was possible in the previous granting period. We anticipate producing 15-40 glaucoma- relevant mutants that will be made available to the glaucoma community as quickly as is feasible. We are confident that continuing to use the power of a phenotype-driven mutagenesis screen in parallel with our unique tools to examine ocular phenotypes will enable us to identify and characterize new genetic factors that contribute to elevated IOP and glaucoma. The new mutants have great potential to transform our understanding of glaucoma. Relevance to Public Health: Glaucoma is one of the leading causes of blindness. Over 20 regions of the human genome have been implicated in glaucoma but very few genes have been identified. Our proposal aims to produce mouse models of human glaucoma to be used as tools to understand the mechanisms of glaucoma, to help identify human glaucoma genes and to test new treatments. ? ? ?
| 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; 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 |
| 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 |
| 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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