The Muller cell is the major non-neuronal cell in the retina, and plays an essential role in normal functioning of the neural retina. The long-term goal of the project is to understand the development, organization and function of Muller cells in retina. The present proposal is concerned with transcriptional responses to extracellular signals, and gene regulatory mechanisms in Muller cells. The studies focus on two genes - the GFAP gene which is upregulated in many retinal disorders, and the CRALBP gene which is expressed only by Mailer cells in retina.
One specific aim i s to identify the signaling molecules responsible for GFAP induction in Muller cells. Since intravitreal injection of growth factors and cytokines such as bFGF and CNTF results in rapid GFAP induction in Muller cells, the proposed studies will examine whether these substances act directly on Muller cells.
A second aim i s to identify the cis regulatory sequences required for Muller cell-specific, GFAP transcription, using deletion analysis and transfection assays.
The third aim i s to determine the in vivo specificity of GFAP cis regulatory elements using GFAP-LacZ transgenic mice.
The final aim of the proposal is to characterize the regulatory elements that control CRALBP gene expression in Muller cells. Based on preliminary data, an important goal of the proposal is to determine whether expression of Muller cell-specific genes is primarily determined by negatively-acting cis elements. The proposed studies are important for understanding gene regulatory mechanisms in retina, and should provide valuable information for designing cell-type specific vectors for targeted delivery in gene therapy. The importance of studying Muller cells is emphasized by their involvement in many human retinal diseases leading to blindness.
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