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Prevention of photocarcinogenesis by dietary antioxidant

通过膳食抗氧化剂预防光致癌

基本信息

批准号：
6515268
负责人：
SANTOSH K KATIYAR
金额：
$ 7.18万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-01 至 2003-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Chronic exposure to solar ultraviolet (UV) radiation, particularly UVB (290- 320 nm), is primarily responsible for more than 1,000,000 new cases of nonmelanoma skin cancer each year in the USA alone, making it the most hazardous environmental carcinogen known for humans. Thus, there is an urgent need to develop strategies to prevent the occurrence of these cutaneous malignancies. We and others have previously shown that a polyphenolic fraction isolated from green tea, and particularly its major and the most effective chemopreventive antioxidant constituent (-)-epigallocatechin-3- gallate (EGCG), has remarkable preventive effects against UV-induced skin tumorigenesis in mouse model. The current proposal is designed to define the mechanism through which oral administration of EGCG to SKH-l hairless mice prevents photocarcinogenesis. The central hypothesis to be tested in this proposal is that UVB exposure to skin induces oxidative stress, which causes phosphorylation of epidermal growth factor receptor (EGFR) and mitogen- activated protein kinase (MAPK) signaling pathways leading to the induction of photocarcinogenic events. The corollary to our hypothesis is that orally administered dietary antioxidant EGCG from green tea in drinking water to SKH- l hairless mice will prevent UVB radiation-induced oxidative stress, and thus oxidative stress-mediated phosphorylation of EGFR anc PK signaling pathways. The inhibition of UVB-induced oxidative stress-mediated phosphorylation of cellular signaling by EGCG will result in reduction of skin cancer incidence. Following specific aims are proposed to study in this project: (i) to determine the effect of single or multiple UVB exposures on cutaneous oxidative stress, and preventive effects by dietary antioxidant EGCG against UVB-induced oxidative stress, and (ii) to determine the effect of UVB-induced oxidative stress-caused phosphorylation of EGFR, and MAPK such as extracellular signal-regulated kinase (ERK1/2), JNK and p38 signaling pathways in vivo mouse skin. Preventive effects of EGCG will be determined on UVB- induced oxidative stress mediated phosphorylation of these cell-signaling events. Validation of this hypothesis would help in developing novel dietary intervention approaches and future strategies to prevent solar UV radiation- induced skin cancer development, which may result to protect and prolong the human health and lives.

描述（由申请人提供）：长期暴露于太阳紫外线 (UV) 辐射，特别是 UVB (290- 320 nm），主要负责超过 1,000,000 个新病例仅在美国每年就有非黑色素瘤皮肤癌发生，使其成为最常见的皮肤癌人类已知的危险环境致癌物。因此，有一个紧急的需要制定策略来预防这些皮肤问题的发生恶性肿瘤。我们和其他人之前已经证明，多酚从绿茶中分离出来的部分，特别是其主要和最重要的部分有效的化学预防抗氧化剂成分 (-)-表没食子儿茶素-3- 没食子酸酯（EGCG），对紫外线引起的皮肤有显着的预防作用小鼠模型中的肿瘤发生。当前的提案旨在定义 SKH-1无毛小鼠口服EGCG的机制防止光致癌。本节要检验的中心假设建议认为，皮肤接触 UVB 会引起氧化应激，从而导致表皮生长因子受体 (EGFR) 和丝裂原的磷酸化激活蛋白激酶 (MAPK) 信号通路导致诱导光致癌事件。我们的假设的推论是口头从饮用水中的绿茶中提取膳食抗氧化剂 EGCG 给 SKH- l 无毛小鼠会预防UVB辐射引起的氧化应激，从而氧化应激介导的 EGFR 和 PK 信号通路磷酸化。抑制 UVB 诱导的氧化应激介导的磷酸化 EGCG 的细胞信号传导将导致皮肤癌发病率降低。本项目建议研究以下具体目标： (i) 确定单次或多次 UVB 暴露对皮肤的影响氧化应激以及膳食抗氧化剂 EGCG 的预防作用 UVB 诱导的氧化应激，以及 (ii) 确定 UVB 诱导的效果氧化应激引起的 EGFR 和 MAPK 磷酸化，例如细胞外信号调节激酶 (ERK1/2)、JNK 和 p38 信号通路体内小鼠皮肤。 EGCG 的预防效果将取决于 UVB- 诱导的氧化应激介导这些细胞信号的磷酸化事件。这一假设的验证将有助于开发新的饮食防止太阳紫外线辐射的干预方法和未来策略诱导皮肤癌的发展，这可能会导致保护和延长人类的健康和生命。