Final Report on “ Cellular and Computational Studies of Tissue Reorganization in Retinitis

Background In the visual system, rods and cones are the primary light sensing cells. Cones are responsible for daytime and color vision whereas rods respond in low light levels. Most mutations responsible for the RP selectively affect rods. However, cones undergo degeneration secondary to the loss of rods, often leading to total blindness. It is estimated that 1/ 4,000 people are affected by RP. Hence, understanding the possibility of cone survival has become a major research challenge in RP. In Dr. Lee’s studies, she found reorganization of the cone mosaic in the S334ter-line-3 rat (a transgenic model developed to express a rhodopsin mutation similar to that found in human RP). The rods’ death triggers a reorganization of the cone mosaic by migration into an orderly array of rings. In their new mosaic, cones survive until old age. The overall hypothesis of this application is that the driving forces for cone migration are due to a complex interaction between rods, cones, Müller cells, and the retinal pigment epithelium (RPE). We hypothesize that trophic factors secreted by these cells mediate this interaction. Based on this hypothesis, we have been able to build a so-far successful computational model for the manifold interaction in the outer retina. This model accounts for and predicts the outcome of a host of cellular and molecular experiments, some of which we have performed preliminarily. Without this model, we could not hand-wave an explanation for many peculiar aspects of the data and thus, they did not make sense. This model, grounded on the field of Systems Biology, is now helping understand the data and make predictions for new experiments. Therefore, with this model, we may be able to understand the cellular mechanisms controlling the mosaic of surviving cones in RP retinas. Consequently, the model may lead to treatment of RP by suggesting strategies for cone repopulation.