EARLY RESPONSE OF CORNEAL EPITHELIUM TO UV-INDUCED DEATH

描述（改编自申请人摘要）：暴露在紫外线下是一种

DESCRIPTION (Adapted from applicant's abstract): Exposure to UV light is a significant environmental and occupational hazard capable of causing acute and chronic inflammatory changes in the cornea. Our long term goal in the corneal epithelium is to characterize the interactions among the cell signaling pathways, which are responsible for UV-induced programmed cell death (apoptosis) and oncogenic changes. We found that an early UV-induced event in these pathways is stimulation of plasma membrane K+ channel activity followed by activation of the stress-induced SEK/JNK signaling pathway, which is a member of the mitogen activated protein kinase (MAPK) superfamily. Interestingly, suppression of UV-induced K+ channel activation completely prevented UV-induced apoptosis through inhibition of UV-induced activation of SEK and JNK kinases. Validation that activation of K+ channel activity is an early event in apoptotic induction is that suppression of K+ channel activity with 4-aminopyridine could not protect corneal epithelial cells from etoposide-induced apoptosis. Thus, we have identified a novel mechanism in which changes in K+ channel activity can modulate SEK/JNK activity and primary rabbit corneal epithelial cell fate. However, nothing is known about other possible interactions linking K+ channel activity to other signaling pathways in the MAPK superfamily as well as other upstream receptors (i.e. EGFR, TNFR1 and CD95/FAS), which are all involved in the control of apoptosis. We hypothesize that activation of EGFR, TNFR1 and CD95/Fas linked signaling pathways in response to UV irradiation is mediated by UV-induced K+ channel hyperactivity. Three specific aims are proposed to determine: 1) what types of K+ channel are in corneal epithelial cells and how K+ channel activity is modulated by UV irradiation; 2) the effect of altered K+ channel activity on activation of EGFR, TNFR1 and CD95/Fas signaling pathways and UV-responding gene expressions; and 3)whether crosstalk occurs in the apoptotic signaling pathways linked to UV-induced K+ channel activation. Our results will shed new insight into the cell signaling interactions that are involved in linking the apoptotic response to UV irradiation. Furthermore therapeutic measures may be identified which could reduce the incidence of UV-induced apoptotic corneal epithelial damage and increases in corneal epithelial susceptibility to infection and diseases.