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Endogenous photosensitizers in skin carcinogenesis

内源性光敏剂在皮肤癌发生中的作用

基本信息

批准号：
7753521
负责人：
ELAINE L JACOBSON
金额：
$ 5.26万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7753521
关键词：
Acute Advanced Glycosylation End Products Amines Animal Model Biological Biological Markers Cells Chemicals Chemoprevention Chemopreventive Agent Chronic 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 Ultraviolet Rays absorption base chromophore crosslink extracellular in vivo in vivo Model innovation irradiation novel pharmacophore photoprotection prototype reconstruction response small molecule tool tumor

项目摘要

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.

本应用程序旨在建立皮肤结构蛋白（角蛋白，胶原蛋白和弹性蛋白）的致病作用