Defining Muller cell domains and the effect that their breakdown has on the retina is an entirely new approach to studying retinal degenerations. Defining an anatomic Muller cell domain has implications for each cell that it contacts, while the functionality of the domain has implications for the Muller cell's role as an active regulator of neuronal processing. If the Muller cell's domain is compromised during degeneration, this could result in aberrant glial and neuronal signaling, insufficient delivery of substrates and/or less efficient removal of waste products, which would ultimately contribute to neuronal degeneration. My goal in this proposal is to test the hypotheses that: (1) the Muller cell forms distinct anatomical domains; (2) domains have functional significance; and (3) breakdown of domains during degeneration contributes to neuronal dysfunction. To label individual Muller cells in vivo, intravitreal injections of adenovirus; will be used to deliver enhanced green fluorescent protein to the Muller cell. Confocal microscopy will be used to image the Muller cell and identify its domain within the retina. Once the domain is anatomically defined, calcium imaging studies will be performed via the caging and uncaging of calcium within Muller cells. Calcium signaling in adjacent Muller cells as well as photoreceptor cells will be measured. Changes in light-evoked photoreceptor cell responses within the Muller cell domain as well as pH will be measured and compared to changes outside the domain. Finally, a model of retinal degeneration will be used to test the above effects in Muller cells that have become reactive or gliotic. The role the Muller cell plays in health and in disease will be determined based on domain structure within the retina. How this affects photoreceptor cell function will also studied. Thus, establishing the central role that the Muller cell plays in retinal health and disease may provide a potential target for new clinical therapies that might delay or prevent neuronal loss and help to preserve vision.
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