The glaucomas are a complex series of diseases, all of which have the eventual endpoint of retinal ganglion cell (RGC) death and blindness. They have diverse phenotypic and genetic risk factors including elevated intraocular pressure (IOP), decreased central corneal thickness (CCT), increased axial length, increased age, and increased cup-to-disc ratio of the optic nerve head. The present project uses the BXD RI mouse strain set to characterize two specific ocular phenotypes associated with human glaucoma - CCT and the loss of retinal ganglion cells due to elevation of IOP. These quantitative data will be used to define genomic loci modulating these two phenotypes. An extended analysis will identify candidate genes within the loci and also genetic networks formed by these candidate genes. In collaboration with Dr. Janey Wiggs, we will use a bidirectional translational approach to link common genetic loci modulating these phenotypes in the mouse to humans with glaucoma. Our collaborative group, including experts in mouse and human genetics, has already identified genomic loci in the mouse that modulate naturally occurring variation in CCT and also axonal loss induced by experimentally increased IOP. Our preliminary analysis of genetic modulators of CCT defines one significant locus on Chr 13 and several candidate genes, one of which is Lyst. In the human GWAS LYST has a significant association with glaucoma. In addition we have identified one significant locus on Chr 18 that is associated with axon loss following elevation of IOP. One gene in this locus (Smad2) has an association with normotensive glaucoma in humans. Combining our genomic analysis in the mouse with data from the human GWAS studies has allowed our group to identify two genes (LYST and SMAD2) that may contribute to human glaucoma. We will expand this approach to expose additional candidate genes and gene networks in the mouse related to human glaucoma. These studies will also allow us to define in the mouse the complex interactions between different genes associated with human glaucoma.

Public Health Relevance

The underlying causes of the majority of glaucoma cases are not known and this limits the treatment options to one, lowering the intraocular pressure. This proposal will identify gene loci that modulate glaucoma severity and will expand the list of genes that are known to contribute to glaucoma. In addition, we will define mouse models that will aid in understanding the complex genetic interactions associated with glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY017841-05A1
Application #
8500956
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Chin, Hemin R
Project Start
2006-12-10
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$375,000
Indirect Cost
$125,000
Name
University of Tennessee Health Science Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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Templeton, Justin P; Wang, XiangDi; Freeman, Natalie E et al. (2013) A crystallin gene network in the mouse retina. Exp Eye Res 116:129-40
Templeton, Justin P; Freeman, Natalie E; Nickerson, John M et al. (2013) Innate immune network in the retina activated by optic nerve crush. Invest Ophthalmol Vis Sci 54:2599-606
Munguba, Gustavo C; Geisert, Eldon E; Williams, Robert W et al. (2013) Effects of glaucoma on Chrna6 expression in the retina. Curr Eye Res 38:150-7
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Sullivan, Timothy A; Geisert, Eldon E; Templeton, Justin P et al. (2012) Dose-dependent treatment of optic nerve crush by exogenous systemic mutant erythropoietin. Exp Eye Res 96:36-41
Lu, Hong; Wang, Xusheng; Pullen, Matthew et al. (2011) Genetic dissection of the Gpnmb network in the eye. Invest Ophthalmol Vis Sci 52:4132-42
Lu, Hong; Li, Liyuan; Watson, Edmond R et al. (2011) Complex interactions of Tyrp1 in the eye. Mol Vis 17:2455-68
Pan, Ye; Geisert, David F; Orr, William E et al. (2011) The effects of a CD81 null mutation on retinal pigment epithelium in mice. Neurochem Res 36:569-73

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