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.
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