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.
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.
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|Struebing, Felix L; King, Rebecca; Li, Ying et al. (2018) Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse. Exp Eye Res 169:61-67|
|Wang, Jiaxing; Struebing, Felix L; Ferdous, Salma et al. (2018) Differential Exon Expression in a Large Family of Retinal Genes Is Regulated by a Single Trans Locus. Adv Exp Med Biol 1074:413-420|
|Wang, Jiaxing; Li, Ying; King, Rebecca et al. (2018) Optic nerve regeneration in the mouse is a complex trait modulated by genetic background. Mol Vis 24:174-186|
|King, Rebecca; Li, Ying; Wang, Jiaxing et al. (2018) Genomic Locus Modulating IOP in the BXD RI Mouse Strains. G3 (Bethesda) 8:1571-1578|
|Struebing, Felix L; King, Rebecca; Li, Ying et al. (2018) Transcriptional Changes in the Mouse Retina after Ocular Blast Injury: A Role for the Immune System. J Neurotrauma 35:118-129|
|Struebing, Felix L; Wang, Jiaxing; Li, Ying et al. (2017) Differential Expression of Sox11 and Bdnf mRNA Isoforms in the Injured and Regenerating Nervous Systems. Front Mol Neurosci 10:354|
|Struebing, Felix L; Lee, Richard K; Williams, Robert W et al. (2016) Genetic Networks in Mouse Retinal Ganglion Cells. Front Genet 7:169|
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|Grossniklaus, Hans E; Geisert, Eldon E; Nickerson, John M (2015) Introduction to the Retina. Prog Mol Biol Transl Sci 134:383-96|
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