Grant: $342,786 - National Institutes of Health - Jul. 17, 2009
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Award Description: Muller 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 Muller cells. At present very little is known about what molecular changes occur following activation, and how activation impacts on Muller 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 Muller cells using Florescence Activated Cell Sorter. The proposal has three specific aims. The first specific aim is to determine the role of Muller 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. However, the nature of this neuroprotective signaling is not known. We propose to examine two ideas - whether CNTF- treated Muller cells release neuroprotective agents, which act to prevent photoreceptor loss or whether CNTF treatment leads to metabolic changes in Muller cells that promotes neuroprotection. The second specific aim is to determine gene expression changes induced in microglia by CNTF. These findings should help dissect Muller cell-microglia-photoreceptor interactions; thus, providing a molecular explanation for CNTF action as well as a rational basis for CNTF therapy. The third specific aim will utilize microarray data from FACS-sorted Muller cells to explore the functional changes in retinal degeneration 1 (rd1) mice, a mouse model of rapid retinitis pigmentosa. Alterations in normal Muller cell functions will be determined by biochemical, cell biological, and physiological assays. Molecular characterization of activated Muller cells can be expected to lead to innovative, therapeutic treatments for photoreceptor degenerations, whose aim is to stimulate Muller cells to produce neuroprotective agents that prevent photoreceptor death, and to restore Muller cell's neuron-supportive functions lost in the diseased retina. PUBLIC HEALTH RELEVANCE: 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 Muller (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 Muller cells to produce neuroprotective agents that prevent photoreceptor death, and to restore Muller cell's neuron-supportive functions lost in the diseased retina.
Project Description: As defined in the Award Description field
Jobs Summary: American Recovery and Reinvestment Act funds have significantly aided the research mission of Northwestern University by providing salary compensation for individuals directly involved in research, both at Northwestern and at consortium institutions, as well as at the vendor organizations who provide goods and services in support of that mission. Northwestern has employed a standard methodology for determining jobs created or retained, based on guidance presented by OMB. Jobs are reported in aggregate for the grant, comprised of calculated figures for hourly and salaried employees at Northwestern plus the reported jobs created or retained by subrecipients. The number of Northwestern hourly employees will be calculated as the number of hours charged to the grant divided by the standard hours in a full-time schedule for the period. The number of Northwestern salaried employees will be calculated based on the paid effort charged to the ARRA grant divided by the total salary. The time span used for determining FTEs created/retained varies by grant or contract. It is based on the number of days between the award start date (or pre-spending start date) and quarter end date (or award end date). Following is a list of descriptions for jobs created or retained, in whole or in part, by this ARRA funded project: Professor, Research Technologist 1. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 17, 2009. Help expand these official descriptions using the wiki below.