In most higher animals, including ourselves, injury to axons within the central nervous system (CNS) leads to the death of axotomized neurons, probably due to los of target-derived growth factors. The long term goal of this research is to elucidate the mechanisms by which growth factors prevent the death of axotomized ganglion cells in the retina. Do to its great accessibility, and ability to regenerate, the frog optic nerve is an excellent model system in which to address this question. We have shown that application of basic fibroblast growth factor (bFGF) to the cut optic nerve greatly increases the number of surviving retinal ganglion cells (RGCs). This project aims firstly to localize the site of action of bFGF in the optic nerve and determine whether it exerts its survival effect on RGCs by acting directly upon their axons, or by acting on optic nerve glia which proliferate and/or release other survival-promoting substances.
The second aim of this project is to determine the manipulations of the accessible frog optic nerve to determine whether the mitogen-activated protein kinase calcium entry. The third and final aim is to study some of the changes in gene expression induced in the retina and optic nerve by bFGF application to the optic nerve stump. Using a combination of immunocytochemistry, Western blotting, in situ hybridization and quantitative RT-PCR we will study how bFGF alters the expression of the growth-associated protein GAP-43 in RGCs, and of the cell death- preventing protein, Bcl-2, Basic FGF may have therapeutic benefit in limiting or preventing neuronal death in a variety of neurodegenerative disorders. However, its effects are not always beneficial, so it is essential to gain a deeper understanding of the cellular and molecular mechanisms by which bFGF promotes neuronal survival.
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