PROJECT SUMMARY
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.