Endogenous photosensitizers in skin carcinogenesis

内源性光敏剂在皮肤癌发生中的作用

• 批准号: 7332241
• 负责人: ELAINE L JACOBSON
• 金额: $ 29.35万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7332241
• 关键词: Acute; Advanced Glycosylation End Products; Amines; Animal Model; Biological; Biological Markers; Cells; Chemicals; Chemoprevention; Chemopreventive Agent; Chronic; Class; Collagen; Data; Dermis; Dose; Elastin; Epidermis; Event; Experimental Models; Extracellular Matrix Proteins; Extracellular Protein; Human; In Vitro; Intervention; Keratin; Lead; Light; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Nature; New Agents; Pathway interactions; Photosensitization; Photosensitizing Agents; Preventive Intervention; Production; Proteins; Radiation; Reactive Oxygen Species; Research; Role; Simulate; Singlet Oxygen; Skin; Skin Carcinogenesis; Skin Tissue; Solar Energy; Source; Stress; Structural Protein; Testing; Therapeutic; Thick; Tissue Model; absorption; base; chromophore; crosslink; extracellular; in vivo; in vivo Model; innovation; irradiation; novel; pharmacophore; photoprotection; photoprotective agent; prototype; reconstruction; response; small molecule; tool; tumor

DESCRIPTION (provided by applicant): This application aims to establish a causative role of skin structural proteins (keratin, collagen, and elastin) as endogenous UV-sensitizers in skin photodamage and evaluates modulation of these novel targets for chemoprevention of photocarcinogenesis and photoaging. Photooxidative stress initiated by solar irradiation of 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 this hypothesis reconstructed epidermis, dermis, and full thickness human skin tissue equivalents will be used 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 depletion, will be tested as a prototype chemopreventive agent and derivatized for optimal topical delivery (aim 4). The efficacy of the lead quencher of photoexcited states will be tested in an animal model of photocarcinogenesis. This study will validate endogenous structural skin components as novel molecular targets for chemoprevention in skin photocarcinogenesis and photoaging and lead to a new class of photoprotective agents.

描述（由申请人提供）：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）作为内源性紫外线敏化剂在皮肤光损伤中的致病作用，并评价这些新靶点对光致癌和光老化化学预防的调节作用。由太阳辐射引起的内源性敏化剂的光氧化应激是皮肤光损伤的关键机制，但是负责光驱动的活性氧（ROS）产生的光动力非DNA发色团的分子性质是未知的。本申请中总结的试验数据支持以下假设：仅包含在皮肤细胞外基质蛋白中的UV发色团是有效的内源性光敏剂。为了检验这一假设，将使用重建的表皮、真皮和全层人类皮肤组织等同物来定量控制酶和非酶来源的蛋白质UV发色团（目的1）。将确定响应于全部和部分太阳紫外光的依赖于敏化剂和独立的ROS产生，并通过直接化学分析验证结果（目标2）。已建立的光氧化应激的分子和细胞生物标志物将作为敏化剂含量和辐射剂量的函数进行评估。将研究已知的光致癌和光老化生物标志物的光敏化增强（目的3）。将评估光激发态物理猝灭剂作为一类新型局部化学预防剂抑制重建人体皮肤中的敏化光损伤的治疗潜力。将照射具有受控敏化剂含量的重建的人类皮肤，并将评价原型猝灭剂作为光激发态的直接分子拮抗剂的化学预防潜力。一种新的仲胺药效团，其通过激发态分子和单线态氧的物理失活而没有化学消耗来保护人类皮肤细胞免受光敏作用，将作为原型化学预防剂进行测试并衍生化以获得最佳局部递送（目的4）。将在光致癌作用的动物模型中测试光激发态的铅猝灭剂的功效。本研究将验证内源性结构皮肤成分作为皮肤光致癌和光老化化学预防的新分子靶点，并导致一类新的光保护剂。