Post-Developmental Function of the RPE-Produced VEGF

Vascular endothelial growth factor (VEGF) is a potent growth factor and plays a pivotal role in the pathogenesis of ocular vascular diseases, including wet forms of age-related macular degeneration (AMD). However, VEGF may also be beneficial and is now recognized as a neurotrophic factor. The focus of this study is to determine the function of the VEGF made by a major retinal supporting cell, retinal pigment epithelium (RPE), in photoreceptor survival. It has been suggested that the RPE-derived VEGF may be responsible for the stability and function of the major retinal blood circulation, and abnormality in this circulation will eventually lead to photoreceptor degeneration, a situation similar to that in geographic atrophy (dry AMD). To dissect the function of the RPE-derived VEGF, we have developed a cutting-edge genetic system in mice, which permits the deletion of the VEGF gene specifically in the RPE at a time of our choosing. This unique feature provides an unprecedented advantage over other known genetic systems and allows us to delete the VEGF gene in the mouse RPE after development and investigate the function of the RPE-derived VEGF in adults. The experiments proposed in this application will improve the understanding of the pathophysiology of age-related macular degeneration (AMD). Our results may also be used to develop new therapeutics to prevent vision loss in AMD patients and improve current therapeutics for wet AMD and other ocular vascular diseases. To achieve our goal, we will first delete the VEGF gene in the RPE after development. We will then determine the time course and function of the RPE-derived VEGF in photoreceptor survival with functional and morphological analyses. Finally, we will determine if we can speed up our future studies by applying light-induced oxidative stress and testing its effect on our mouse model.