Endogenous photosensitizers in skin carcinogenesis

本申请旨在确定皮肤结构蛋白（角蛋白、胶原蛋白和弹性蛋白）作为 I皮肤光损伤中的内源性紫外线增敏剂，并评估这些新靶点对 光致癌和光老化的化学预防。太阳辐射引发的光氧化应激 内源性致敏物是皮肤光损伤的关键机制，但内源性致敏物的分子性质是光损伤的主要原因。 光动力非DNA发色团负责光驱动的活性氧物质的产生 (ROS)不明申请中总结的试验数据支持以下假设： 仅包含在皮肤的细胞外基质蛋白中的是有效的内源性光敏剂。测试 这一假设重建的表皮、真皮和全层人类皮肤组织等同物将是 用于定量控制酶和非酶来源的蛋白质紫外发色团 “（目标1）。敏感剂依赖和独立的ROS生产响应总和分馏太阳能 将测定紫外光，并通过直接化学分析验证结果（目的2）。建立 光氧化应激的分子和细胞生物标志物将作为敏化剂的函数进行评估 含量和辐射剂量。光敏化增强已知的光致癌生物标志物， 将研究光老化（目标3）。光激发态物理猝灭剂的治疗潜力， 一类新的局部化学预防剂，用于抑制重建中的敏化光损伤， 将评估人皮肤。将对具有受控致敏剂含量的重建人体皮肤进行辐照 和原型猝灭剂作为光激发的直接分子拮抗剂的化学预防潜力 将对各国进行评估。一种新的仲胺药效团，可保护人类皮肤细胞免受 通过激发态分子和单线态氧的物理失活而没有化学物质的光敏化 Idepletion将作为原型化学预防剂进行测试，并衍生为最佳局部给药 一（目标4）。光激发态的铅猝灭剂的功效将在以下动物模型中测试： 光致癌作用。本研究将验证内源性结构皮肤成分作为新的分子 I靶向皮肤光致癌和光老化的化学预防，并导致一类新的 光保护剂。

This application aims to establish a causative role of skin structural proteins (keratin, collagen, and elastin) as I endogenous UV-sensitizers in skin photodamage and evaluates modulation of these novel targets for I chemoprevention of photocarcinogenesis and photoaging. Photooxidative stress initiated by solar irradiation Iof endogenous sensitizers is a key mechanism of skin photodamage, but the molecular nature of the photodynamic non-DNA chromophores responsible for light-driven production of reactive oxygen species (ROS) is unknown. Pilot data summarized in the application support the hypothesis that UV chromophores contained exclusively in extracellular matrix proteins of skin are potent endogenous photosensitizers. To test Ithis hypothesis reconstructed epidermis, dermis, and full thickness human skin tissue equivalents will be Iused to allow quantitative control of protein UV-chromophores of both enzymatic and non-enzymatic origin "(aim 1). Sensitizer-dependent and independent ROS production in response to total and fractionated solar UV light will be determined and results will be validated by direct chemical analyses (aim 2). Established molecular and cellular biomarkers of photooxidative stress will be assessed as a function of sensitizer content and radiation dose. Photosensitized enhancement of known biomarkers of photocarcinogenesis and photoaging will be studied (aim 3). The therapeutic potential of physical quenchers of photoexcited states as a novel class of topical chemopreventive agents for suppression of sensitized photodamage in reconstructed human skin will be evaluated. Reconstructed human skin with controlled sensitizer content will be irradiated and the chemopreventive potential of prototype quenchers as direct molecular antagonists of photoexcited states will be evaluated. A novel secondary amine pharmacophore, which protects human skin cells against photosensitization by physical deactivation of excited state molecules and singlet oxygen without chemical Idepletion, will be tested as a prototype chemopreventive agent and derivatized for optimal topical delivery I(aim 4). The efficacy of the lead quencher of photoexcited states will be tested in an animal model of Iphotocarcinogenesis. This study will validate endogenous structural skin components as novel molecular Itargets for chemoprevention in skin photocarcinogenesis and photoaging and lead to a new class of Iphotoprotective agents.