Glaucoma is the leading cause of irreversible blindness in the world. While elevated intraocular pressure (IOP) is a major risk factor, damage and death of retinal ganglion cells (RGCs) underlies visual field loss. However, a thorough understanding of this disease is a major challenge because its genetic basis is heterogeneous and it represents a family of age-related disorders resulting from intersecting gene-regulated pathophysiologic networks. We propose to continue to use the BXD (C57BL/6 x DBA/2J) family of recombinant inbred (RI) lines of mice as a genetic reference panel (GRP) and to combine our work with human genome wide association studies (GWAS), to uncover and clarify the genetic heterogeneity that underlies optic nerve (ON) damage. We have had recent success using this combined approach in the regulation of intraocular pressure (IOP). We are very well positioned to take the next step and apply this approach to define cellular targets of RGC damage and death. We propose to uncover phenotypic diversities of glaucoma-related ON damage and uncover common underlying mechanisms that are shared with IOP modulation. Our long-term research goal is to identify disease mechanisms and develop neuroprotective therapies to preserve retinal health in patients at risk for glaucoma. Our overall objective is to identify novel gene products and related mechanisms that lead to glaucomatous endophenotypes using multi-dimensional genetic analyses, cross-species comparisons (mouse, rat and human) and validation using novel murine glaucoma models. Our central hypothesis is that molecular processes leading to glaucoma associated-endophenotypes, such as elevated IOP and ON damage, are shared across species, and that species comparisons can uncover common underlying mechanisms, and efficient testing of targeted glaucoma therapeutics. In the current investigation, we perform a systematic analysis of ON damage, and an additional species?rat. We will mine the extensive databases of IOP and ON damage that we are generating for more than 70 BXD strains across five age cohorts with the goal of defining new models of glaucoma. An overall strength of this proposal is the combination of cutting-edge systems genetics methods, species comparisons of glaucoma phenotypes, and a strong interdisciplinary team that includes investigators with extensive experience in systems genetics, glaucoma, GWAS in human and rats, and advanced computational methods. To test our hypothesis, we will perform the following thress studies: 1) Identify the candidate gene on chromosome 12 that modulates ON damage; 2) Determine if modulation of IOP and/or ON damage is shared across rodent species; and 3) Identify novel spontaneous glaucoma models through a comprehensive analysis of our enlarged BXD GRP of 100 or more BXD strains. The outcomes of these studies will define novel genes and molecular networks that underlie glaucoma-associated phenotypes and also provide unique glaucoma models for future analysis. These results are expected to fundamentally advance the field of glaucoma disease mechanisms and enable targeted therapeutic development.

Public Health Relevance

Glaucoma is the leading cause of irreversible blindness in the world and a thorough understanding of this disease is a major challenge because its genetic basis is heterogeneous, and it likely represents a family of disorders resulting from intersecting gene-regulated pathophysiologic pathways. Our goals are to: identify candidate gene(s) that modulate optic nerve damage; determine if regulation of intraocular pressure and/or optic nerve damage are shared across species; and identify novel spontaneous glaucoma models. These outcomes will fundamentally advance the field of glaucoma disease mechanisms and enable targeted therapeutic development.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY021200-05
Application #
9648959
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Liberman, Ellen S
Project Start
2011-02-01
Project End
2023-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38103
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
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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
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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
Mulligan, Megan K; Dubose, Candice; Yue, Junming et al. (2013) Expression, covariation, and genetic regulation of miRNA Biogenesis genes in brain supports their role in addiction, psychiatric disorders, and disease. Front Genet 4:126

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