Genetic Modulation of Glaucoma

Summary

Principal Investigator: Lu Lu
Abstract: 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.
Funding Period: 2011-06-01 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. pmc Genetic pathways regulating glutamate levels in retinal Müller cells
    Monica M Jablonski
    Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Neurochem Res 36:594-603. 2011
  2. pmc Genetic dissection of the Gpnmb network in the eye
    Hong Lu
    Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong, China
    Invest Ophthalmol Vis Sci 52:4132-42. 2011
  3. pmc Complex interactions of Tyrp1 in the eye
    Hong Lu
    Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA
    Mol Vis 17:2455-68. 2011
  4. pmc Bilateral subcortical heterotopia with partial callosal agenesis in a mouse mutant
    G D Rosen
    Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
    Cereb Cortex 23:859-72. 2013
  5. pmc Innate immune network in the retina activated by optic nerve crush
    Justin P Templeton
    Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA
    Invest Ophthalmol Vis Sci 54:2599-606. 2013
  6. pmc Genetic modulation of the iris transillumination defect: a systems genetics analysis using the expanded family of BXD glaucoma strains
    Shankar Swaminathan
    Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA
    Pigment Cell Melanoma Res 26:487-98. 2013

Research Grants

  1. Interleukin-6 and Retinal Ganglion Cell Degeneration in Glaucoma
    Rebecca M Sappington; Fiscal Year: 2013
  2. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
  3. Novel Therapy and Mechanisms in Glaucoma
    Tonia S Rex; Fiscal Year: 2013
  4. Characterization of RGC death susceptibility alleles
    Robert W Nickells; Fiscal Year: 2013
  5. Chinese American Eye Study
    Rohit Varma; Fiscal Year: 2013
  6. ENVIRONMENTAL APPROACHES TO PREVENTION
    Paul J Gruenewald; Fiscal Year: 2013
  7. Defining and Treating Written Language Disabilities
    VIRGINIA WISE BERNINGER; Fiscal Year: 2013
  8. Molecular Genetics of Dominant Neovascular Inflammatory Vitreoretinopathy
    Vinit B Mahajan; Fiscal Year: 2013
  9. Optic Nerve Aging and Glaucoma
    Thasarat Vajaranant; Fiscal Year: 2013
  10. Genetic Analysis of Murine Chronic Hypoxia-Induced Pulmonary Hypertension
    William C Nichols; Fiscal Year: 2013

Detail Information

Publications7

  1. pmc Genetic pathways regulating glutamate levels in retinal Müller cells
    Monica M Jablonski
    Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Neurochem Res 36:594-603. 2011
    ....
  2. pmc Genetic dissection of the Gpnmb network in the eye
    Hong Lu
    Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong, China
    Invest Ophthalmol Vis Sci 52:4132-42. 2011
    ..To use a systematic genetics approach to investigate the regulation of Gpnmb, a gene that contributes to pigmentary dispersion syndrome (PDS) and pigmentary glaucoma (PG) in the DBA/2J (D2) mouse...
  3. pmc Complex interactions of Tyrp1 in the eye
    Hong Lu
    Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA
    Mol Vis 17:2455-68. 2011
    ....
  4. pmc Bilateral subcortical heterotopia with partial callosal agenesis in a mouse mutant
    G D Rosen
    Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
    Cereb Cortex 23:859-72. 2013
    ..The discovery of a novel mutation with strong pleiotropic anatomical and behavioral effects provides an important new resource for dissecting molecular mechanisms and functional consequences of errors of neuronal migration...
  5. pmc Innate immune network in the retina activated by optic nerve crush
    Justin P Templeton
    Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA
    Invest Ophthalmol Vis Sci 54:2599-606. 2013
    ..We have used transcriptome profiling in the mouse to identify a network of genes involved in innate immunity that is present in the normal retina and that is activated by optic nerve crush (ONC)...
  6. pmc Genetic modulation of the iris transillumination defect: a systems genetics analysis using the expanded family of BXD glaucoma strains
    Shankar Swaminathan
    Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA
    Pigment Cell Melanoma Res 26:487-98. 2013
    ..Our model accounted for 71-88% of the explained variance of the TID phenotype across the age bins. These results demonstrate that along with Tyrp1 and Gpnmb, Oca2, Myo5a, Prkcz, and Zbtb20 modulate the TID in an age-dependent manner. ..

Research Grants30

  1. Interleukin-6 and Retinal Ganglion Cell Degeneration in Glaucoma
    Rebecca M Sappington; Fiscal Year: 2013
    ..We propose a series of studies to examine the potential of the inflammatory cytokine interleukin-6 as a therapeutic target to rescue RGCs in glaucoma. ..
  2. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  3. Novel Therapy and Mechanisms in Glaucoma
    Tonia S Rex; Fiscal Year: 2013
    ..EpoR76E blocks synapse targeting by C1Q, thus preserving normal synaptic connections and visual function. These hypotheses will be tested in the DBA/2J, and additional novel mouse models of glaucoma. ..
  4. Characterization of RGC death susceptibility alleles
    Robert W Nickells; Fiscal Year: 2013
    ..Finding and characterizing these alleles will lead to better diagnosis and treatment regimes for individuals with glaucoma. ..
  5. Chinese American Eye Study
    Rohit Varma; Fiscal Year: 2013
    ..These findings are also likely to be of increasing public health importance, as the societal burden of age-related eye disease will likely increase with the aging of this rapidly growing segment of the US population. ..
  6. ENVIRONMENTAL APPROACHES TO PREVENTION
    Paul J Gruenewald; Fiscal Year: 2013
    ....
  7. Defining and Treating Written Language Disabilities
    VIRGINIA WISE BERNINGER; Fiscal Year: 2013
    ..The proposed multidisciplinary research has practical significance for improving diagnosis and providing more effective services which may lower such risks. ..
  8. Molecular Genetics of Dominant Neovascular Inflammatory Vitreoretinopathy
    Vinit B Mahajan; Fiscal Year: 2013
    ..Discovery of the gene and downstream signals in this disease will help to understand and treat these blinding diseases. ..
  9. Optic Nerve Aging and Glaucoma
    Thasarat Vajaranant; Fiscal Year: 2013
    ..More broadly, this work serves as a foundation for a future line of investigations into sex-differences and non-hormonal mechanisms of optic nerve aging and risks for glaucoma. ..
  10. Genetic Analysis of Murine Chronic Hypoxia-Induced Pulmonary Hypertension
    William C Nichols; Fiscal Year: 2013
    ..A better understanding of the genetics of right heart dysfunction in these diseases will likely enable new therapies to prevent and/or to treat right heart failure, resulting in reduced morbidity and mortality. ..
  11. Development of Retinal Bipolar Cells
    Benjamin E Reese; Fiscal Year: 2013
    ..These experiments will reveal the determinants of nerve cell number and morphology, clarifying our understanding of retinal development, as well as identifying gene polymorphisms that may contribute to retinal disease. ..