Flaum Eye Institute

Richard Libby, Ph.D.

Assistant Professor
Department of Ophthalmology

 

Research Overview

Glaucoma is a complex group of diseases where many different genetic and environmental factors conspire to cause vision loss. While there are many different causes of glaucoma, the ultimate cause of vision loss in all glaucomas is the death of retinal ganglion cells (RGCs), the output neurons of the retina. Therefore, glaucoma is a neurodegeneration. Our lab focuses on the neurobiology of glaucoma. Primarily, we use mouse models of glaucoma and advanced mouse genetics to probe the pathophysiology of glaucoma. Specifically, we are interested in understanding the molecular processes that lead to RGC death in glaucoma and why are RGCs more likely to die in some patients than in others

Cell Death Pathways Active in Glaucoma

To date, no molecules are known to be necessary for glaucomatous neurodegeneration nor has the initial molecular trigger(s) been identified. Identifying the molecular pathways required for RGC death in glaucoma will answer fundamental questions about neuronal pathophysiology and will identify potential therapeutic targets for the treatment of optic neuropathies. To determine the molecular degeneration cascades active in glaucoma we are taking two approaches. (1) Candidate gene analysis. The neurotrophic deprivation pathway (as one example) has been implicated as a critical pathway for glaucomatous RGC death. At both the protein and RNA level, we found that components of this pathway (e.g. BIM, JUN, and JNKs) are present in glaucomatous DBA/2J mice, suggesting that this pathway contributes to RGC death. Currently using our knowledge of the key mediator of somal apoptosis in DBA/2J glaucoma (BAX activation) and the other molecules that have been impacted in glaucoma, we are attempting to ‘back track’ our way up the RGC degeneration pathway. Eventually we hope this approach will lead to a complete identification of the somal and axonal degeneration pathways and to the initial molecular trigger(s) in glaucoma. (2) Genomic analysis. We are also using microarray analysis to investigate DBA/2J glaucoma. Microarray analysis has the potential to identify molecules involved in glaucomatous neurodegeneration that could not be predicted from current knowledge. In these experiments, gene expression changes at various, distinct stages of DBA/2J glaucomatous neurodegeneration are being examined.

Neuronal Susceptibility Factors

Elevated intraocular pressure is the best known risk factor for glaucoma. However, there is extensive patient variability in what constitutes pathogenic intraocular pressure (IOP), suggesting that other susceptibility factors are important in glaucoma. Therefore, even though glaucoma is clearly associated with IOP, susceptibility factors intrinsic to the RGCs and/or other retinal cells are likely critical mediators of glaucomatous neurodegeneration. We are attempting to define the genetic susceptibility factors that conspire with IOP to determine the probability of developing glaucoma and/or the severity of glaucoma. For instance we have shown that deficiencies in BAX gene dosage (a key molecule in the glaucomatous RGC degeneration pathway) can slow RGC loss in glaucomatous mice. These data suggest that allelic differences in components of the RGC degeneration pathway may contribute to glaucoma pathology. Also, we have been addressing the effect of blood pressure on glaucoma by backcrossing a null allele of angiotensin receptor 1 (Agtr1; deficiency in Agtr1 lowers blood pressure in mice) into DBA/2J. Low blood pressure in DBA/2J mice significantly increases the rate of glaucomatous neurodegeneration. Therefore, it appears that many diverse genetic factors can contribute to glaucomatous neurodegeneration and that the DBA/2J mouse is an effective tool in identifying these factors.

Selected Publications

1. Libby, R.T., D.D. Hunter and W.J. Brunken. Developmental expression of laminin ß2 in rat retina: further support for a role in rod morphogenesis. Investigative Ophthalmology and Visual Science. 1996; 37:1651-1661.

2. Libby, R.T., Y. Xu, L.M. Selfors, W.J. Brunken and D.D. Hunter. Identification of the cellular source of laminin ß2 in adult and developing vertebrate retinae. Journal of Comparative Neurology. 1997; 389:655-670.

3. Libby, R.T., C.R. Lavalle, G.W. Balkema, W.J. Brunken and D.D. Hunter. Disruption of laminin ß2 chain production causes alterations in morphology and function in the central nervous system. Journal of Neuroscience. 1999; 19:9399-9411.

4. Libby, R.T., M.F. Champliaud, Y. Xu, E.P. Gibbons, M. Koch, R.E. Burgeson, D.D. Hunter and W.J. Brunken. Laminin expression in adult and developing retinae: evidence for two novel central nervous system laminins. Journal of Neuroscience. 2000; 20:6517-6528.

5. Libby, R.T. and K.P. Steel. Electroretinographic analysis of shaker1 mice: a mouse model for Usher syndrome type 1B. Investigative Ophthalmology and Visual Science. 2001; 42:770-778.

6. Kros, C.J., W. Marcotti, S.M. van Netten, T.J. Self, R.T. Libby, S.D.M. Brown, G.P. Richardson and K.P. Steel. Reduced climbing and increased slipping adaptation in cochlear hair cells of mice with Myo7a mutations. Nature Neuroscience. 2002; 5:41-47.

7. Warner, C.L., A. Stewart, J.P Luzio, K.P. Steel, R.T. Libby, J. Kendrick-Jones and F. Buss. Loss of myosin VI reduces secretion and the size of the Golgi in fibroblasts from Snell's waltzer mice. Embo Journal. 2003; 22:569-579.

8. Libby, R.T., J. Kitamoto, R.H. Holme, D.S. Williams and K.P. Steel. Cdh23 mutations in the mouse are associated with retinal dysfunction but not retinal degeneration. Experimental Eye Research. 2003; 77:731-740.

9. Libby, R.T., R.S. Smith, O.V. Savinova, A. Zabaleta, J.E. Martin, F.J. Gonzalez and S.W.M. John. Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science. 2003; 299:1578-81.

10. Gibbs, D., C. Lillo, S.M. Azarian, J. Kitamoto, A.E. Klomp, K.P. Steel, R.T. Libby, and D.S. Williams. Role of myosin VIIa and Rab27a in the distribution of RPE melanosomes. The Journal of Cell Science. 2004; 117:6473-6483.

11. Libby, R.T., C. Lillo, J. Kitamoto, D.S. Williams and K.P. Steel. Myosin Va is required for normal photoreceptor synaptic activity. The Journal of Cell Science. 2004; 117:4509-4515.

12. Anderson, M.G., R.T. Libby*, D.B. Gould, R.S. Smith and S.W.M. John. High-dose Radiation Treatment Prevents Neurodegeneration in Glaucoma. Proceedings of the National Academy of Sciences of the USA. 2005; 102:4566-4571. *co-first author.

13. Kitamoto J, R.T. Libby*, D. Gibbs, K.P. Steel and D.S. Williams. Myosin VI is required for normal photoreceptor function. Experimental Eye Research. 2005; 81:116-120. *co-first author.

14. Libby R.T., Y Li , O.V. Savinova, J. Barter, R.S. Smith, R.W. Nickells and S.W.M. John. Susceptibility to neurodegeneration in glaucoma is modified by Bax gene dosage. PLoS Genetics. 2005; 1:e4.

15. Akobs, T.C., R.T. Libby, Y. Ben, S.W. John and R.H. Masland. Ganglion cell degeneration is topological but not cell type specific in a mouse model of glaucoma. The Journal of Cell Biology. 2005; 171:313-325.

16. Libby, R.T., M.G. Anderson, I-H. Pang, Z.H. Robinson, O.V. Savinova, I.M. Cosma, A. Snow, L.A. Wilson, R.S. Smith, A.F. Clark and S.W.M. John. Inherited glaucoma in DBA/2J mice: pertinent disease features for studying the neurodegeneration. Visual Neuroscience. 2005; 22:637-648.

17. Anderson M.G., R.T. Libby, M. Mao, I.M. Cosma, L.A. Wilson, R.S. Smith and S.W.M. John. Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma.  BMC Biology. 2006; 4:20.

18. Howell, G.H., R.T. Libby, L.A. Wilson, I.M. Cosma, R.S. Smith, M.G. Anderson and S.W.M. John. Absence of glaucoma in DBA/2J mice homozygous for wild-type versions of Gpnmb and Tyrp1. BMC Genetics.  2007; 8:45.

19. Libby, R.T., G.H. Howell, I.-H. Pang, O.V. Savinova, A.K. Mehalow, J.W. Barter, R.S. Smith, A.F. Clark and S.W.M. John.  Inducible nitric oxide synthase, Nos2, does not mediate optic neuropathy and retinopathy in the DBA/2J glaucoma model.  BMC Neuroscience. 2007; 8:108.

20. Howell, G.H., R.T. Libby*, T.C. Jacobs, R.S. Smith, F.C. Phalan, J.W. Barter, J. Barbay, J.K. Marchant, N. Mahesh, V. Porciatti, A.V. Whitmore, R.H. Masland and S.W.M. John. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma.  Journal of Cell Biology. 2007; 179:1523-1537.
*co-first author.

21. Ding, Q., H. Chen, X. Xie, R.T. Libby, N. Tian, L. Gan. BARHL2 differentially regulates the development of retinal amacrine and ganglion neurons. Journal of Neuroscience. 2009; 29:3992-4003.

22)  Scoles D., D.C. Gray, J.J. Hunter, R. Wolfe, B.P. Gee, Y.Geng, B.D. Masella, R.T. Libby, S. Russell, D.R. Williams and W.H. Merigan. In-vivo imaging of retinal nerve fiber layer vasculature: imaging - histology comparison. BMC Ophthalmology. 2009; 9:9.

Reviews

1. Libby, R.T., D.D. Hunter and W.J. Brunken. Roles of the extracellular matrix in retinal development and maintenance. Ed. M.E. Fini, In Results and Problems in Cell Differentiation: Vertebrate Eye Development. 2000; 31:115-140.

2. Libby, R.T. and K.P. Steel. The roles of unconventional myosins in hearing and deafness. Ed. G. Banting & S.J. Higgins, In Essays in Biochemistry, Molecular Motors. 2000; 35:159-173.

3. Whitmore, A.V., R.T. Libby and S.W.M. John. Glaucoma: thinking in new ways - a role for autonomous axonal self-destruction and other compartmentalised processes? Progress in Retinal and Eye Research. 2005; 24:639-662.

4. Libby, R.T., D.B. Gould, M.G. Anderson and S.W.M. John. Complex genetics of glaucoma susceptibility. Annual Reviews of Genomics and Human Genetics. 2005; 6:15-44

5. Howell, G.H., R.T. Libby, and S.W.M. John.  Mouse Genetic Models: An ideal system for understanding glaucomatous neurodegeneration and neuroprotection.  Eds. C. Nucci, N. Osborne, G. Bagetta and L. Cerulli. In Progress in Brain Research.  Glaucoma: An open-window to neurodegeneration and Neuroprotection. 2008; 173:303-321.

6. Libby, R.T. and D.B. Gould. Endoplasmic reticulum stress as a primary pathogenic mechanism leading to age-related macular degeneration. Proceedings of the XIII International Symposium on Retinal Degeneration.  In the Press.


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