MOiler cells, the predominant glial cells in the vertebrate retina, play an essential role in maintaining neuronal health and activity. Recent work on retinal glia has also shown that virtually every retinal disease is associated with 'activation'of MOiler cells At present very little is known about what molecular changes occur following activation, and how activation impacts on MOiler cell role in retinal homeostasis and retinal disease pathogenesis. The proposed studies ?are designed to answer these questions. These studies are made possible for the first time by the development of a method to purify MOiler cells using Florescence Activated Cell Sorter. The proposal has two specific aims. The first specific aim is to determine the role of MOiler cells in photoreceptor neuroprotection mediated by Ciliary neurotrophic factor (CNTF). CNTF appears to be the most effective and mutation-independent, neuroprotective agent that slows photoreceptor loss in inherited retinal degenerations. Recently, a phase I clinical trial demonstrated the safety of CNTF in retinitis pigmentosa (RP) patients, and phase II trials are underway. Unfortunately, we do not now how CNTF rescues photoreceptors, but it appears that CNTF might act by stimulating Muller cells. We propose to examine (1) whether CNTFtreated Muller cells release neuroprotective agents, which act to prevent photoreceptor loss;and (2) to determine gene expression changes induced in microglia by CNTF. These findings should help dissect MOiler cell-microglia-photoreceptor interactions;thus, providing a molecular explanation for CNTF action as well as a rational basis for CNTF therapy. Molecular characterization of activated MOiler cells can be expected to lead to innovative, therapeutic treatments for photoreceptor degenerations, whose aim is to stimulate MOiler cells to produce neuroprotective agents that prevent photoreceptor death, and to restore MOiler cell's neuronsupportive functions lost in the diseased retina.
Retinal neurodegenerative diseases are characterized by progressive loss of rod and cone photoreceptors leading eventually to blindness. Recent investigations suggest that retinal disease pathogenesis might be influenced by changes in the activity of support cells, known as glial cells, that are associated with retinal neurons. The present proposal will examine the contribution of M?ller (glial) cells in the pathogenesis of retinitis pigmentosa and age-related macular degeneration. Molecular characterization of activated Muller cells can be expected to lead to innovative, therapeutic treatments for photoreceptor degenerations, whose aim is to stimulate M?ller cells to produce neuroprotective agents that prevent photoreceptor death, and to restore Muller cell's neuron-supportive functions lost in the diseased retina
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