Retinal ischemia is defined as an arrest of blood flow and reduction of oxygen supply to the retina. Ischemic damage to the retina is a common pathological factor in a number of blinding diseases in humans including central retinal artery and vein occlusions, diabetes, retinopathy of prematurity, and glaucoma to name a few. Although ischemia-induced damage to the retina is known to lead to irreversible loss of ganglion cells, the pathophysiology underlying this process is not clearly understood. The long-term goal of this laboratory is to determine the triggering mechanisms that lead to ganglion cell loss in retinal ischemia because a complete understanding of the disease process will help us in designing preventative strategies to rescue ganglion cells in sight-threatening ischemic retinal diseases. Preliminary findings, using a central retinal ligation model in mice, support the hypothesis that retinal ischemia induces expression of matrix metalloproteinase gelatinase B (MMP-9) by cells in the ganglion cell layer; that MMP-9 mediates degradation of extracellular matrix (ECM) composing of retinal inner limiting membrane (ILM); and that this leads to apoptosis of ganglion cells. Experiments are now proposed to determine (a) the timing and localization of MMPs in the ganglion cell layer, (b) the cell types that synthesize these MMPs in the ganglion cell layer, (c) the role of a particular MMP that leads to ganglion cell loss, (d) the ECM components that are degraded in the ILM, and (e) the neuroprotective effects of MMP inhibition on ganglion cell loss. The proposed studies would not only facilitate our understanding of the mechanisms that underlie ischemia-induced ganglion cell loss in this model system, but in the long-run would also help us in designing neuroprotective strategies to prevent loss of retinal ganglion cells in blinding ischemic retinal diseases.
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