EARLY RESPONSE OF CORNEAL EPITHELIUM TO UV-INDUCED DEATH

描述(改编自申请人的摘要)：暴露在紫外线下是一种 重大的环境和职业危害，能够造成急性和 角膜的慢性炎症改变。我们在角膜上的长期目标 上皮细胞是用来表征细胞信号之间相互作用的 负责紫外线诱导的程序性细胞死亡的途径 (细胞凋亡)和致癌变化。我们发现，早期紫外线诱导的事件在 这些途径是刺激质膜K通道活性的后续途径 通过激活应激诱导的SEK/JNK信号通路，这是一种 丝裂原活化蛋白激酶(MAPK)超家族的成员。 有趣的是，完全抑制紫外线诱导的钾通道激活 通过抑制紫外线诱导的细胞凋亡来预防紫外线诱导的细胞凋亡 SEK和JNK激酶。确认K通道活性的激活是一种 诱导细胞凋亡早期事件是抑制K通道活性 4-氨基吡啶不能保护角膜上皮细胞 依托泊苷诱导细胞凋亡。因此，我们已经确定了一种新的机制 K通道活性的哪些变化可以调节SEK/JNK活性和原发 兔角膜上皮细胞命运。然而，对其他人却一无所知 K通道活性与其他信号通路之间可能的相互作用 在MAPK超家族以及其他上游受体(即EGFR、TNFR1)中 和CD95/Fas)，它们都参与了细胞凋亡的调控。我们 假设EGFR、TNFR1和CD95/Fas信号通路的激活 紫外光诱导的钾通道介导的紫外光反应途径 多动症。提出三个具体目标来确定：1)什么类型的 K通道存在于角膜上皮细胞以及K通道的活性如何 2)钾通道活性改变对心肌细胞的影响。 EGFR、TNFR1和CD95/Fas信号通路的激活与紫外线反应 基因表达；3)细胞凋亡信号中是否存在串扰 与紫外线诱导的钾通道激活有关的通路。我们的结果将带来新的变化 深入了解细胞信号相互作用，这些信号相互作用涉及 紫外线照射下的细胞凋亡反应。此外，治疗措施可能是 确定哪些药物可以减少紫外线诱导的角膜细胞凋亡的发生率 角膜上皮损伤和角膜上皮易感性增加 感染和疾病。

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.