Research Project
9442009
Irreversible vision loss is one of the top ten disabilities worldwide and is responsible for reduced quality of life and a substantial burden on national healthcare systems. Although proliferation of neural tissue is not typical in adult mammals, triggering proliferation of neurons in adults could potentially reverse the effects of retinal disease. Previous studies from this lab have demonstrated that eye drop application of the ?7 nAChR agonist, PNU-282987, to the mammalian eye leads to neurogenesis in the adult retina. This current proposal is designed to examine the mechanism associated with this effect and to assess whether an increase of new retinal neurons affects visual function. Based on preliminary studies, the experiments designed under specific aim #1 are designed to demonstrate that PNU-282987 induces neurogenesis in the retina by activating alpha7 nAChRs on retinal pigment epithelium, which release signaling molecules into the neural retina to induce retinal progenitor cells from Muller glia. A rat retinal pigment epithelial cell line will be used to examine which signaling molecules are released from RPE cells to induce neurogenesis from Muller glia. Two specific signaling molecules that will be searched for are Wnt and FGF, as they have been shown to induce retinal progenitor cells from Muller glia in mammalian retina. Transgenic mice that contain tdTomato Muller glia will also be used in this study to examine when retinal progenitor cells emerge from Muller glia, to examine when cells differentiate into neurons and to verify the origin of the new neurons. The second specific aim is designed to assess whether an increase of mitotically active retinal cells affects visual function using ERG and PERG recordings. These electrophysiology studies be conducted before and after treatment with PNU-282987, with and without the ?7 nAChR antagonist, MLA. Changes in ERG waveforms and PERG activity will be used to distinguish activities of different retinal cell types from adult rats. In addition, oscillatory potentials will be assessed for changes to inner retinal activity. The results from this study could have serious implications for reversing vision loss due to traumatic injuries, degenerative retinal disease or age related issues.
