Molecular Mechanisms of UVA apotosis and carcinogenesis

UVA细胞凋亡和癌变的分子机制

• 批准号: 6991757
• 负责人: Zigang Dong
• 金额: $ 29.39万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6991757
• 关键词: AP1 protein; JUN kinase; apoptosis; biological signal transduction; carcinogenesis inhibitor; chemoprevention; enzyme induction /repression; epidermal growth factor; gene mutation; genetically modified animals; growth factor receptors; hairless mouse; human tissue; keratinocyte; kinase inhibitor; laboratory mouse; melanoma; mitogen activated protein kinase; molecular oncology; phosphatidylinositol 3 kinase; protein kinase C; radiation carcinogenesis; radiobiology; skin neoplasms; ultraviolet radiation

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.

描述（由申请方提供）：本项目中待检验的假设是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JNK和p38激酶的激活在UVB诱导的信号转导和皮肤致癌中发挥功能性作用。因此，这些信号分子可用作开发化学预防剂的靶标，以抑制UV/K诱导的非黑素瘤皮肤癌。感兴趣的药剂包括PI-3激酶抑制剂（LY 294002和肌醇六磷酸）、EGFR抑制剂（PD 153035和AG 1478）、JNK抑制剂SP 600125和p38激酶抑制剂SB 202190。本研究的具体目的是：（1）确定UVA诱导的细胞凋亡是否是通过激活人和小鼠角质形成细胞中ATM依赖性p53通路介导的。(2)确定小鼠中Jnkl和Jnk 2的基因敲除是否抑制UVA诱导的皮肤致癌作用。(3)确定在转基因小鼠表皮中磷脂酰肌醇-3（PI-3）激酶突变型p85亚基或显性负性p38激酶（DNp 38）的靶向表达是否抑制UVA诱导的皮肤癌发生。(4)利用已知的靶向皮肤的p38和JNK MAP激酶、EGFR、ATM和PI-3激酶的抑制剂，以确定这些有效的抑制剂是否会在SKH-1无毛小鼠模型中预防UVA诱导的皮肤致癌作用。(5)交叉验证UVA皮肤致癌小鼠和人模型的化学预防靶点。该项目将侧重于UVA诱导的致癌作用和化学预防策略，并将与项目1密切互动，后者将侧重于UVB诱导的致癌作用和化学预防策略。这些临床前研究旨在开发人类皮肤癌化学预防的新策略，并将在项目4中进行测试。