This laboratory has been exploring the mechanisms of immune privilege in the eye and has focused on understanding the regulation of inflammation though apoptosis. We have shown that molecules such as FasL regulate inflammation by inducing apoptosis in lymphoid cells that invade the eye in response to injury or infection. Recently we have found that the mechanisms which control inflammation in the eye also participate in regulating pathologic neovascularization, a major cause of vision loss in patients with age- related macular degeneration (AMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), and corneal disease. In this application, we will extend our studies of apoptosis and immune privilege into area of choroidal neovascularization (CNV), a major cause of vision loss in patients with age related macular degeneration (AMD). We have focused this proposal around the idea that those molecules that protect the eye from inflammation significantly influence blood vessel growth. We believe that our application offers a unique perspective as we combine our expertise in immune privilege, immunology, and cell death to perform these studies. We propose 3 aims: First, we will determine the influence of IL-10 in a mouse model of choroidal neovascularization. We have found that the loss of IL-10, a major anti-inflammatory cytokine, significantly reduces the amount of CNV. Since inflammation can have an impact by promoting angiogenesis, understanding the mechanisms for decreased blood vessel growth in the face of increased inflammation will lead to significant new insights into CNV. Second, we will further explore the role of Fas in endothelial cell biology. Using state of the art technology, we will analyze the pro- and anti-angiogenic properties of the Fas protein. Third, we will further explore the role of FasL expression in the eye in the development of CNV. Using a unique set of experimental tools employing cre/lox technology we will explore the role of a tissue specific knockout of the FasL gene. When completed, our studies will provide a new understanding of angiogenesis in the eye. Relevance to Public Health: AMD is a progressive disease that causes irreversible blindness in nearly 50 million people globally. Our studies examine the impact of the immune system on this blinding eye disorder and will give important information for the design of effective treatments.
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