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 form of age-related macular degeneration (AMD). However, VEGF may also be beneficial and is now recognized as 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 leads 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 VEGF gene in the mouse RPE after development and investigate the function of the RPE-derived VEGF in adult. 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 and 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 a light-induced oxidative stress and testing its effect on our mouse model.
Le Y., Zheng W., Rao P., Zheng L., Anderson R.E., Esumi N., Zack, J.D., Zhu M., (2008) Inducible expression of Cre recombinase in the RPE. Invest Ophthalmol Vis Sci. 49: 1248-1253.
Bai Y., Ma J., Guo J., Wang J., Zhu M., Chen Y., *Le Y. (2009) Müller cell-derived VEGF is a significant contributor to retinal neovascularization (cover article). J. Pathol. 219:446-454.
Ueki Y., Ash J.D., Zhu M., Zheng, L., Le Y. (2009) Expression of Cre recombinase in the retinal Müller cells (cover article). Vis. Res. 49: 615-621. doi:10.1016/j.visres.2009.01.012.
Avasthi P., Watt C., Williams D., Le Y., Li S., Chen C., Frederick J., Baehr, W. (2009) Heterotrimeric Kinesin-II Mediates Trafficking of Membrane Proteins to Cone, but not Rod Outer Segments. J. Neurosci 29:14287-14298.
Le Y. (2010) Computer-assisted semi-quantitative analysis of choroidal density. Adv Exp Med Biol. 664:349-353.
Le, Y. Bai, Y., Zhu, M. and Zheng, L. (2010) Temporal requirement of RPE-derived VEGF in the formation of choroidal vasculature. J. Neurochem. 112: 1584-1592.
Wang J., Xu X., Elliott M.H. *Le Y. (2010) Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage. Diabetes.