In this proposal, we use our enlarged set of BXD recombinant inbred strains to identify gene loci that are involved in modulating the severity of glaucoma. Our approach combines a thorough clinical and laboratory examination, and microarray analysis of the entire set of 81 BXD lines generated over the last 10 years with the express purpose of studying the genetics of eye disease and glaucoma. One of the parental strains of BXD, DBA/2J, develop an age-related glaucoma that is preceded by iris atrophy and pigment dispersion. While mutant alleles of two genes, Tryp1 and Gpnmb, cause the iris disease in D2, the literature strongly suggests that these mutations are not sufficient to cause glaucoma. Specifically, introgression of both mutant alleles onto C57BL/6J, the other parent strain of BXD, results in a marked resistance to optic nerve damage. This indicates that genes other than those that cause pigment dispersion influence the glaucomatous phenotype. The current proposal describes a unique opportunity to define the modifying loci.
In Aim 1, we test the hypothesis that the combined mutations in Tryp1 and Gpnmb are not sufficient to cause all aspects of the glaucoma phenotype. If our hypothesis is true, we expect to see that the severity of disease is not solely dependent on the two mutant alleles. We have already identified multiple BXD strains in which IOP and genetic diplotype are not correlated. As we systematically examine all BXD strains and establish relations between phenotype and diplotype, we fully expect to find additional strains that defy expectations of a simple two-locus disease model.
In Aim 2, we define loci and genes that modulate glaucoma severity. To do so, we will identify and evaluate candidate genes within loci that modulate the severity of the glaucoma phenotype. We will exploit our new whole genome shotgun sequence for D2 (about >50x short read coverage generated at UTHSC in 2009) along with massive whole eye and whole retina expression datasets that we have also generated as a prelude to this work. We expect to efficiently nominate and evaluate candidate glaucoma genes using state-of-the-art bioinformatic methods and conventional molecular assays.
In Aim 3, we use bidirectional translation. We test the translational validity of mouse candidates from Aim 2 using cohorts of human glaucoma patients. Dr. J. Wiggs and colleagues will perform focused gene association studies using candidate glaucoma genes nominated in Aim 2. Specifically, we use association analyses of markers encompassing syntenic regions of human chromosomes. In reciprocal reverse translation, we (MMJ and LL) will evaluate known, new, and candidate glaucoma genes from clinical cohorts and determine if and how these variants are associated with glaucoma- associated traits in BXDs. Combining the top priority gene candidates from both mouse and human glaucoma studies, we will generate molecular and statistical models of susceptibility candidate genes, linked phenotypes, and associated mechanisms.
Glaucoma is a highly prevalent group of diseases that, if uncontrolled, causes irreversible loss of vision. The underlying cause of the disease is not known in the majority of cases, therefore treatment options are limited to lowering the intraocular pressure. Outcomes of our proposed investigations will identify gene loci that modulate glaucoma severity to expand this sparse list of genes that are known to contribute to this disease.
|Lu, Ye; Zhou, Diana; King, Rebecca et al. (2018) The genetic dissection of Myo7a gene expression in the retinas of BXD mice. Mol Vis 24:115-126|
|Chintalapudi, Sumana R; Patel, Need N; Goldsmith, Zachary K et al. (2017) Isolation of Primary Murine Retinal Ganglion Cells (RGCs) by Flow Cytometry. J Vis Exp :|
|Chintalapudi, Sumana R; Maria, Doaa; Di Wang, Xiang et al. (2017) Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. Nat Commun 8:1755|
|Godisela, Kishore Kumar; Reddy, Singareddy Sreenivasa; Kumar, Chekkilla Uday et al. (2017) Impact of obesity with impaired glucose tolerance on retinal degeneration in a rat model of metabolic syndrome. Mol Vis 23:263-274|
|Lu, Hong; Lu, Lu; Williams, Robert W et al. (2016) Iris transillumination defect and its gene modulators do not correlate with intraocular pressure in the BXD family of mice. Mol Vis 22:224-33|
|Chintalapudi, Sumana R; Wang, XiaoFei; Li, Huiling et al. (2016) Genetic and immunohistochemical analysis of HSPA5 in mouse and human retinas. Mol Vis 22:1318-1331|
|Ashbrook, David G; Williams, Robert W; Lu, Lu et al. (2014) Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease. BMC Genomics 15:850|
|Keeley, Patrick W; Zhou, Cuiqi; Lu, Lu et al. (2014) Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics. Proc Natl Acad Sci U S A 111:9295-300|
|Swaminathan, Shankar; Lu, Hong; Williams, Robert W et al. (2013) Genetic modulation of the iris transillumination defect: a systems genetics analysis using the expanded family of BXD glaucoma strains. Pigment Cell Melanoma Res 26:487-98|
|Rosen, G D; Azoulay, N G; Griffin, E G et al. (2013) Bilateral subcortical heterotopia with partial callosal agenesis in a mouse mutant. Cereb Cortex 23:859-72|
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