Molecular Mechanisms of Retinal Ganglion Cell Death

The only treatment for glaucoma is to treat the primary risk factor for this disease, which is an elevated intraocular pressure (IOP). Research efforts have been focused on finding alternative treatments that will directly affect the survival of the retinal ganglion cells. Dr. Nickells has been defining the molecular biology of the process of ganglion cell death, with the goal that some of the biochemical events that occur in a dying ganglion cell could be manipulated to increase the chance of cell survival. When ganglion cells receive a stimulus to die, they activate a series of biochemical events that leads to their eventual suicide. These events can be broken into semi-sequential steps. Strategies aimed at blocking late steps in the process do not appear to offer promising treatments. Therefore, Dr. Nickells has chosen to study the earliest events in the cell death process. This is the period when normal gene expression is turned off. Dr. Nickells’ earlier work has discovered that three known genes active in ganglion cells are turned off with nearly identical kinetics in dying cells. The first part of this study is to develop a more comprehensive method for identifying additional such genes. The second part of the project is to investigate the mechanism for turning these genes off, and to test possible pharmacological approaches for intervening in this process. The third part of the study is to find out if blocking the early down-regulation of gene expression has any positive impact on cell survival. If this can be accomplished, then blocking the early events in ganglion cell death may be a viable target for new treatments in glaucoma. This project is a continuation of Dr. Nickells’ earlier BrightFocus-funded work, begun in 1999.