The nm3342 mouse may be the first clinically appropriate animal model for studying serous detachment and CSR. An early goal of our study will be to determine if there are gene differences in the RPE and choroidal between mutant and wild type mice that may disrupt regulation and allow for fluid leakage. in In these mutants, the choroidal or RPE cells may be abnormal, tight junctions that seal the extracellular space between cells may be affected, or there may be RPE cell death . We will also determine if the mutation itself causes abnormalities in the neural retina or if abnormalities only arise after retinal detachment. Rhegmatogenous detachment (where fluid flows through a hole or break in the retina) creates many rapid cellular changes in the retina. Whether serous detachments cause similar changes is unknown. Current observations in human patients with CSR suggest degenerative changes in the photoreceptor layer, but their nature is unknown. We will determine if the photoreceptor degeneration and cell death occurs in the mice and if there is neuronal or glial remodeling that may predict mechanisms for visual imperfections in human CSR patients. An upregulation of many immune response genes and the activation of microglial cells occur after rhegmatogenous detachment. We will determine if similar responses occur after detachment in the nm3342 mice. Thus, microarray analysis to compare gene expression profiles in retinas of mutant and wild type mice before and after the detachments occur will be a critical component of this project. Comparisons to gene expression in rhegmatogenous detachments of the same duration will be important as well. We will obtain time-line ocular structural changes in nm3342 mice by high-resolution OCT, a powerful non-invasive technique that will provide additional structural data and help guide the cellular characterization of nm3342. We will do pilot studies to determine if previously tested small molecules resolve detachment in the nm3342 mice, and begin exploring methods for primary cultures of nm3342 RPE cells. The proposed experiments should help us understand the special characteristics of serous retinal detachments, an important first step to understanding CSR in humans.
