Mechanisms of Chemically Induced Photosensitivity

化学诱导光敏性的机制

• 批准号: 7169680
• 负责人: COLIN CHIGNELL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7169680
• 关键词: DNA damage; Smith Lemli Opitz syndrome; apoptosis; carcinogen testing; cytotoxicity; electron spin resonance spectroscopy; environmental exposure; epidermal growth factor; fluorescence spectrometry; growth factor receptors; hairless mouse; mitogen activated protein kinase; mutagen testing; photoactivation; photochemistry; photosensitizing agents; protein kinase C; radiation carcinogen; radiation carcinogenesis; radiation hazard; radiobiology; tirapazamine; ultraviolet radiation

The objective of this research project is to elucidate the photochemical and photobiological mechanisms whereby light (UVA and visible radiation) alone or in the presence of endogenous or exogenous photosensitizers exerts either toxic or therapeutic effects. UVA-induced apoptosis in keratinocytes is associated with EGF receptor internalization and down-regulation without receptor phosphorylation and ubiquitination; also UVA exposure causes delayed and sustained activation of ERK MAP kinase. We have identified the skin lipid cholesta-5,7,9(11)-trien-3 beta-ol (9-DDHC) as the putative agent responsible for UVA-induced skin photosensitivity in Smith-Lemli-Opitz syndrome patients. 9-DDHC generates singlet oxygen and superoxide upon UVA irradiation and is phototoxic to keratinocytes. A2E, a lipid degradation product found in lipofuscin granules deposited in the retina, is photoprotective in the young eye but may be phototoxic in older eyes.

该研究项目的目的是阐明光化学和光生物学机制，光（UVA和可见辐射）单独或在内源性或外源性光敏剂存在下发挥毒性或治疗作用。 UVA 诱导的角质形成细胞凋亡与 EGF 受体内化和下调相关，而无受体磷酸化和泛素化； UVA 暴露也会导致 ERK MAP 激酶延迟和持续激活。我们已经确定皮肤脂质 cholesta-5,7,9(11)-trien-3 beta-ol (9-DDHC) 是导致 Smith-Lemli-Opitz 综合征患者 UVA 诱导皮肤光敏性的推定因素。 9-DDHC 在 UVA 照射下产生单线态氧和超氧化物，并对角质形成细胞具有光毒性。 A2E 是沉积在视网膜的脂褐质颗粒中发现的一种脂质降解产物，对年轻眼睛具有光保护作用，但对老年眼睛可能具有光毒性。