The dynamic process of wound healing is important for maintaining the corneal epithelial layer's normal function that protects the cornea, lens and other underlying ocular structures from damage caused by environmental insults. Ultraviolet (UV) irradiation and other biohazards can induce stress-related cellular responses resulting in damage to the dynamic process of wound healing. Newly obtained data from our lab suggest that that UV stress-induced cellular signaling responses resulting in wound healing retardation in corneal epithelial cells during the early stage before the cells eventually commit apoptosis. Preliminary data suggest that: 1) UV stress-induced cellular response is started by hyperactivation of K+ channels in the membrane; 2) the fast loss of intracellular K+ ions causes cell volume shrinkage; and 3) cell shrinkages induce activations of scaffolding tyrosine kinases (FAK/Src) and MEKK1/4 in the JNK signaling pathway. Subsequently, the activation of JNK cascades in turn increases the phosphorylation level of p53 leading to cell cycle arrest. It is very likely in the corneal epithelium that FAK coordinates signals from inputs of UV-induced volume shrinkage to the JNK signaling pathway. Based on the preliminary study results, we hypothesize that UV stress-induced corneal epithelial wound healing retardation is regulated by complex crosstalks in signaling processes involving altered cell volume, increased scaffolding tyrosine kinase activity, activated JNK cascades and cell cycle cessation.
Three specific aims will be performed and studied to test this hypothesis: 1) scaffolding tyrosine kinase activation and cytoskeleton reorganization, 2) crosstalk among activations of FAK/Src and MEKK1/4 in the JNK signaling pathway, and 3) effects of signaling components on UV- induced wound healing retardation. We predict that scaffolding protein kinases play important roles in the linkage of UV-induced cell shrinkage and the activation of JNK cascades, resulting in a quick inhibition of cell cycle progression that causes corneal epithelial wound healing retardation. However, UV stress-induced activation of JNK cascades and ONA fragmentation that occurs in a later time are responsible for triggering apoptosis in corneal epithelial cells. Thus, studies of UV stress-induced signaling events provide significant insight for understanding the mechanisms that underlie the corneal epithelial wound healing processes from damages caused by environmental insults. ? ? ?
