Abnormal ocular angiogenesis is often the final step toward vision loss in diseases of the outer retina, such as retinopathy of prematurity, proliferative vitreoretinopathy, diabetic retinopathy, and age-related macular degeneration. In total, these diseases affect over 10 million Americans, and by 2050 it is expected that this number will double. Retinal pigment epithelial (RPE) cells in the outer retina play a significant role in causing and contributing to aberrant angiogenesis. While the mechanisms leading to increased expression of pro-angiogenic factors in the RPE are not entirely clear, evidence suggests that cell-cell contact and intercellular junctions are involved in regulating the expression of pro- and anti-angiogenic factors. Two factors that alter RPE cell-cell contact and junction formation are: 1) RPE cell death, and 2) Increases in mechanical stress. Contact between RPE cells is often lost in combination with pathological conditions, such as geographic atrophy, choroidal neovascularization (CNV) in exudative AMD, and even from repeated intravitreal injection of therapeutic drugs. Here we propose to replicate the in vivo loss of intercellular junctions to improve our understanding of the mechanisms of retinal angiogenesis. Specifically, effects of the two factors (cell death and mechanical stress) on normal, aged human RPE cells will be studied. In this application, the following questions are asked: 1) When normal RPE cells experience the loss of cell-cell contact, which angiogenic factors are activated? 2) Can acute and chronic mechanical stress cause RPE cell-cell detachment and induce angiogenic factors? 3) Can an increase in angiogenesis be linked to specific intercellular junction proteins? and 4) Do pharmaceutical treatments reduce abnormal angiogenesis in in vitro models of retinal disease? The PI and her group are uniquely equipped to contribute to bridging the gap between in vivo and in vitro studies by developing engineering methods to isolate and control specific factors that affect the ability of RPE cells to form intercellular junctions to determine their role in angiogenic growth factor expression. Performing this research will significantly improve our understanding of mechanisms leading to abnormal angiogenesis and vision loss. In this R15 application, undergraduate and graduate students will be relied upon throughout and exposed to new areas of biomedical research, preparing them for health-related graduate work and careers. The results of this work and the effect of this funding will have a definitive positive impact on both retinal disease research and on the students at Utah State University.
The goal of this research is to investigate the relationship between intercellular junction formation and the expression of pro and anti-angiogenic markers. Studying the cause of abnormal blood vessel growth in the retina is important for understanding the initiation and progression of retinal diseases, as well as testing and developing new treatments.