UV INDUCED AND PERK MEDIATED SIGNALING PATHWAYS

点击翻译按钮获取中文摘要

The aim of this proposal is to study the role of PERK (PKR-like ER kinase) in UV-induced translational inhibition and apoptosis. Previous studies have shown that UV can induce apoptosis which may be important in the responses of skin to UV damage. The proposed study will focus on the translational regulation resulting in UV-radiation by evaluating the role of a newly-discovered translational regulator, PERK in UV induced stress signaling pathways. The proposed research will investigate the mechanism of UV-induced translational regulation and its role in NFkB activation and cell apoptosis. The research proposed in Specific Aim 1 will determine the detailed mechanism inhibition of protein synthesis for UV-induced inhibition of protein synthesis by determining the roles of PERK activation and EIF2alpha phosphorylation in UV-induced translational regulation pathways. The proposed research will also determine the pathways that lead to the translation inhibition upon UV irradiation and the mechanisms for UV-induced PERK activation and EIF2alpha phosphorylation. The research proposed in Aim 2 will investigate the roles of PERK and translational regulation in UV-induced NFkB activation by demonstrating whether UV UV-induced reduction in IkB is truly regulated at the translational level. The proposed research will also determine the pathway that leads to the reduction in IkB on UV irradiation and demonstrate whether PERK regulates NFkB activation. Aim 3 will determine the role of PERK in UV-induced apoptosis by systematically identifying apoptotic genes that are regulated at the translational level after UV irradiation. The proposed research will also investigate the upstream and downstream signaling pathways that are related to UV-induced and PERK-mediated cell death.