Molecular Mechanisms of UVA apotosis and carcinogenesis

项目描述（由申请人提供）：本项目拟验证的假设是，ATM、磷脂酰肌醇-3激酶（PI-3激酶）、表皮生长因子受体（EGFR）、MAP激酶JNKs和p38激酶的激活在UVB诱导的信号转导和皮肤癌发生中发挥功能作用。因此，这些信号分子可以作为开发化学预防药物的靶点，以抑制UV/k诱导的非黑色素瘤皮肤癌。感兴趣的药物包括PI-3激酶抑制剂（LY294002和六磷酸肌醇），EGFR抑制剂（PD153035和AG1478）， JNKs抑制剂SP600125和p38激酶抑制剂SB202190。具体目的是解决这一假设：(1)确定uva诱导的细胞凋亡是否通过激活人类和小鼠角质形成细胞中的atm依赖性p53通路介导。(2)确定小鼠Jnkl和Jnk2基因敲除是否抑制uva诱导的皮肤癌变。(3)确定在转基因小鼠表皮中靶向表达磷脂酰肌醇-3 （PI-3）激酶突变体p85亚基或显性阴性p38激酶（DNp38）是否能抑制uva诱导的皮肤癌。(4)利用已知的靶向皮肤的p38和JNK MAP激酶、EGFR、ATM和PI-3激酶抑制剂，在SKH-1无毛小鼠模型中确定这些有效抑制剂是否能预防uva诱导的皮肤癌。(5)交叉验证UVA皮肤癌变小鼠模型和人模型的化学预防靶点。该项目将专注于uva诱导的致癌和化学预防策略，并将与项目1密切互动，项目1将专注于uvb诱导的致癌和化学预防策略。这些临床前研究旨在开发人类皮肤癌化学预防的新策略，这些策略将在项目4中进行测试。

DESCRIPTION (provided by applicant): The hypothesis to be tested in this project is that activation of ATM, phosphatidylinositol-3 kinase (PI-3 kinase), epidermal growth factor receptor (EGFR), MAP kinase JNKs and p38 kinases play a functional role in UVB induced signal transduction and skin carcinogenesis. Therefore these signaling molecules can be used as targets for the development of chemopreventive agents to inhibit UV/k-induced non-melanoma skin cancers. The agents of interest include PI-3 kinase inhibitors (LY294002 and inositol hexaphosphate), EGFR inhibitors (PD153035 and AG1478), JNKs inhibitor SP600125 and p38 kinase inhibitor SB202190. The Specific Aims to address the hypothesis are to: (1) Determine whether UVA-induced apoptosis is mediated by activation of an ATM-dependent p53 pathway in human and mouse keratinocytes. (2) Determine whether genetic knockout of Jnkl and Jnk2 in mice inhibits UVA-induced skin carcinogenesis. (3) Determine whether targeted expression of a mutant p85 subunit of phosphatidylinositol-3 (PI-3) kinase or a dominant negative p38 kinase (DNp38) in the epidermis of transgenic mice inhibits UVA-induced skin carcinogenesis. (4) Utilize known inhibitors of p38 and JNK MAP kinases, EGFR, ATM and PI-3 kinases targeted to the skin to determine whether these effective inhibitors will prevent UVA-induced skin carcinogenesis in an SKH-1 hairless mouse model. (5) To cross validate the targets for chemoprevention between mouse and human models of UVA skin carcinogenesis. This project will focus on UVA-induced carcinogenesis and chemoprevention strategies, and will closely interact with Project 1, which will focus on UVB-induced carcinogenesis and chemoprevention strategies. These preclinical studies are designed to lead to the development of new strategies for the chemoprevention of human skin cancers, which will be tested in Project 4.