Endogenous photosensitizers in skin carcinogenesis

这项应用旨在确定皮肤结构蛋白(角蛋白、胶原和弹性蛋白)的致病作用 I内源性紫外线增敏剂在皮肤光损伤中的作用，并评估这些新靶点对 一、化学预防光致癌和光老化。太阳辐射引发的光氧化应激 IOF内源性增敏剂是皮肤光损伤的关键机制，但 光动力非DNA发色团负责光驱动产生活性氧物种 (ROS)未知。在申请中总结的试点数据支持紫外线生色团的假设 强效的内源性光敏剂仅存在于皮肤的细胞外基质蛋白中。为了测试 在这一假说中，重建的表皮、真皮和全层人类皮肤组织的等价物将是 用于定量控制酶来源和非酶来源的蛋白质UV-发色团 “(目标1).依赖感光剂和独立产生的ROS对总太阳能和分光太阳能的反应 将确定紫外光，并通过直接化学分析验证结果(目标2)。已建立 光氧化应激的分子和细胞生物标记物将作为增敏剂的功能进行评估 含量和辐射剂量。已知的光致癌变生物标志物的光敏增强 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药物抑制重建的敏化光损伤 将对人类皮肤进行评估。具有受控致敏剂含量的重建的人体皮肤将被照射 以及作为光激发直接分子拮抗剂的原型猝灭剂的化学预防潜力 将对各州进行评估。一种新的次级胺药效团，可保护人类皮肤细胞免受 激发态分子物理失活和无化学单线态氧的光敏作用 Idepletion，将作为一种原型化学预防药物进行测试，并进行衍生化以实现最佳的局部给药 I(目标4)。光激发态铅猝灭剂的有效性将在 光致癌变。这项研究将验证内源性皮肤结构性成分是否为新的分子 I化学预防皮肤光致癌和光老化的靶点，并导致一类新的 光防护剂。

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.