The open environment of the ocular surface is continuously subject to the entry of pathogens and other foreign agents. The molecular mechanisms which provide for protection of ocular surface cells from bystander injury resulting from host responses that may be elicited by these agents are incompletely understood. Unexpectedly, it was found that corneal and conjuctival epithelia express high levels of the decay-accelerating factor (DAF or CD55), the membrane cofactor protein (MCP or CD46), and a membrane inhibitor of reactive lysis (MIRL or CD59), three surface regulatory proteins that play critical roles in protecting blood cells from autologous complement-mediated damage. Remarkably, the expression levels of the three proteins on the corneal and conjuctival surfaces are higher that those on blood cells or measured elsewhere in the body. In previous work, the investigators have shown that 1) DAF is synthesized by both ocular surface and lacrimal glandular-cells, 2) a glycoinositol phospholipid anchor-cleaved and previously underdescribed form of the protein is secreted into tears, 3) all of the C3 regulatory activity in tear fluid resides in these molecules, and 4) surface DAF molecules are shed onto contact lenses and can be depleted by certain bacteria. In this application they propose to 1) fully characterize DAF, CD59, and MCP proteins in ocular tissues structurally, functionally, metabolically, 2) develop an experimental animal model to investigate the importance of the ocular surface regulatory proteins in protecting the corneal and conjuctival surface from injury physiologically, and 3) examine ocular infections, ocular complications of contact lens wear, ocular tumors, and other clinical settings in which immune and inflammatory processes lead to ocular surface damage for abnormalities of the three proteins. The studies should provide new insights concerning the manner in which the ocular surface circumvents attack by host effector responses and could yield new information regarding pathogenic mechanisms underlying ocular diseases.
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