Glaucomatous disorders leading to optic neuropathies cause blindness in humans. These diseases cause primary damage to the ganglion cell axons initiating secondary demise of ganglion cells. The applicant's recent findings in either axotomized or glaucomatous (elevated intraocular pressure or IOP) rats show that ganglion cell death in adult eye is apoptotic. In optic nerve- axotomized eye, apoptotic death is controllable by providing neurotrophic factors which activate receptors, thereby signaling pathways within the cells that stimulate gene expression and protein synthesis. The applicants have induced a secondary glaucoma in rats by selective blocking of episcleral venous drainage. Resultant elevated IOP is stable for many weeks. It is proposed to study in controlled elevated IOP eyes and optic nerve-axotomized eye: (1) temporal sequence of ganglion cell death and (2) the rescuing effort by applying various neurotrophic factors. Since the applicants have demonstrated that plasmid DNA can be inserted in vivo in adult ganglion cells and that transfected cells produce specific proteins, the experimental strategy will be to use specific proto-oncogenes to transfect ganglion cells in vivo in optic nerve-axotomized and glaucomatous (elevated IOP) animals. These genes will constitutively stimulate the internal domains of Trk receptors present on the cells, thereby alleviating ligand-specific stimulation of the receptor. This rat model for glaucomatous eyes showing apoptotic cell death of retinal ganglion cells is stated to offer unique opportunities to establish evaluation of cell death and/or rescue. The approach of trophic factor application and gene therapy will be tested for effectiveness in rescuing cell death using various anatomical and biochemical methods. The proposed studies will serve as an experimental model system for development of technology necessary to use direct application of trophic factors and genetic manipulations to treat disorders of optic neuropathy specially elevated IOP related glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011295-02
Application #
2020026
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1995-12-08
Project End
1999-11-30
Budget Start
1996-12-01
Budget End
1997-11-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
New York Medical College
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Qin, Qiong; Patil, Kiran A; Gronert, Karsten et al. (2008) Neuroprotectin D1 inhibits retinal ganglion cell death following axotomy. Prostaglandins Leukot Essent Fatty Acids 79:201-7
King, Wayne Michael; Sarup, Vimal; Sauve, Yves et al. (2006) Expansion of visual receptive fields in experimental glaucoma. Vis Neurosci 23:137-42
Sarup, Vimal; Patil, Kiran; Sharma, S C (2004) Ciliary neurotrophic factor and its receptors are differentially expressed in the optic nerve transected adult rat retina. Brain Res 1013:152-8
Patil, Kiran; Sharma, Sansar C (2004) Broad spectrum caspase inhibitor rescues retinal ganglion cells after ischemia. Neuroreport 15:981-4
Qin, Qiong; Patil, Kiran; Sharma, Sansar C (2004) The role of Bax-inhibiting peptide in retinal ganglion cell apoptosis after optic nerve transection. Neurosci Lett 372:17-21
Ahmed, F A; Hegazy, K; Chaudhary, P et al. (2001) Neuroprotective effect of alpha(2) agonist (brimonidine) on adult rat retinal ganglion cells after increased intraocular pressure. Brain Res 913:133-9
Ko, M L; Hu, D N; Ritch, R et al. (2001) Patterns of retinal ganglion cell survival after brain-derived neurotrophic factor administration in hypertensive eyes of rats. Neurosci Lett 305:139-42
Ahmed, F A; Chaudhary, P; Sharma, S C (2001) Effects of increased intraocular pressure on rat retinal ganglion cells. Int J Dev Neurosci 19:209-18
Ahmed, F A; Ingoglia, N A; Sharma, S C (2001) Axon resealing following transection takes longer in central axons than in peripheral axons: implications for axonal regeneration. Exp Neurol 167:451-5
Ko, M L; Hu, D N; Ritch, R et al. (2000) The combined effect of brain-derived neurotrophic factor and a free radical scavenger in experimental glaucoma. Invest Ophthalmol Vis Sci 41:2967-71

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