Damage to the corneal epithelium renders the cornea vulnerable to infection and compromises its optical functions. Rapid repair is critical. Much remains unknown of how repair is regulated but multifunctional molecules that accelerate wound healing and protect against infection are likely to be particularly important and have great potential as exogenously applied therapeutic agents. After injury the corneal epithelium expresses human beta-defensin-2 (hBD-2). Our preliminary data also indicate that expression of the cathelicidin LL-37 is upregulated. hBD- 2 and LL-37 are peptides with antimicrobial activity capable of stimulating migration and proliferation of various human cells. Thus, they are uniquely placed to promote healing and provide protection against infection at the ocular surface. The following general hypothesis is proposed : hBD-2, LL-37 and their rodent homologues, are multifunctional molecules which promote ocular surface wound healing and protect against infection. Cultured human corneal epithelial cells, human corneas in organ culture, ocular pathogens and animal models will be used to address the following specific aims:
Specific Aim 1 : Hypothesis : LL-37 is upregulated by cytokines after injury and stimulates corneal epithelial cell migration, proliferation and cytokine secretion via formyl peptide receptor-like 1 (FPRL1).
Specific Aim 2 : Hypothesis : Animal models in which the rodent homologues of hBD-2 and LL-37 have been eliminated show impaired corneal epithelial healing in vivo.
Specific Aim 3 : Hypothesis : beta-Defensin-2 and cathelicidin are effective against ocular pathogens in vitro and mice in which the hBD-2/LL-37 homologues have been knocked out show increased susceptibility to P. aeruginosa. These studies will help delineate the roles of defensins and cathelicidin at the ocular surface and will provide valuable insight in to their potential as therapeutic agents. ? ? ?
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