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MECHANISMS FOR CHRONIC UVR-INDUCED DAMAGE TO SKIN

紫外线引起的皮肤慢性损伤的机制

基本信息

批准号：
6632628
负责人：
IRENE KOCHEVAR
金额：
$ 30.7万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-07-10 至 2005-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6632628
关键词：
cellular pathology elastases enzyme activity enzyme inhibitors fibrillin fibroblasts histology human tissue keratinocyte laboratory mouse laboratory rat light adverse effect neutrophil skin disorder solar radiation ultraviolet radiation

项目摘要

Solar elastosis is a hallmark of photoaging, the accumulated response of skin to injury caused by years of environmental exposure to solar ultraviolet irradiation (UVR). In solar elastosis, the elastic fibers in the dermis are greatly increased in amount and appear to be thickened and contain large amorphous areas. Despite this increase in elastin, the skin shows decreased elasticity and loss of resilience. Increased synthesis and degradation are part of the dermal remodeling resulting from chronic sun exposure. The processes involved in stimulating synthesis of tropoelastin by fibroblasts in response to UVR are only inadequately understood. This application addresses mechanisms whereby chronic UVR exposure may increase elastin by synthesis of tropoelastin and fibrillin, major components of elastin fibers. The overall goal is to identify key control points in order to devise protective measures. The Specific Aims of this application are: 1) to test the hypothesis that reactive oxygen species (ROS) produced by neutrophils enhance development of solar elastosis in murine skin that is chronically treated with UV irradiation. 2) to test the hypothesis that increased elastase activity in response to chronic UV irradiation up-regulates tropoelastin and fibrillin synthesis by dermal fibroblasts thereby contributing to the development of solar elastosis, and 3) to determine whether UVR absorbed by keratinocytes or fibroblasts induce the synthesis of tropoelastin and fibrillin by dermal fibroblasts. The Specific Aims will be addressed using mouse strains that are deficient in the generation of ROS by neutrophils, or are deficient in the release of neutrophil elastase or alpha-1 protease inhibitor. Elastase inhibitors will also be employed in vivo. In vitro experiments using human dermal fibroblasts grown in contracted collagen gels or skin equivalents will be used to define mechanisms for the phenomena observed in vivo.

日光弹性组织变性是光老化的一个标志，是累积的反应因长年暴露于阳光环境而造成的皮肤损伤紫外线照射（UVR）。在日光性弹性变性中，弹性纤维真皮的数量大大增加，并且看起来增厚并含有大的非晶区域。尽管弹性蛋白增加，但皮肤仍表现出弹性降低和恢复力丧失。增加合成和降解是长期日晒造成的真皮重塑的一部分接触。刺激原弹性蛋白合成的过程包括成纤维细胞对紫外线反应的了解还不够充分。这应用解决了慢性紫外线暴露可能增加的机制由原弹性蛋白和原纤维蛋白合成而成的弹性蛋白，原弹性蛋白和原纤维蛋白是弹性蛋白的主要成分纤维。总体目标是确定关键控制点，以便设计保护措施。该应用程序的具体目标是： 1) 检验以下假设：中性粒细胞产生的活性氧 (ROS) 促进长期用紫外线照射治疗的小鼠皮肤的日光性弹性组织变性。 2) 检验弹性蛋白酶活性增加的假设慢性紫外线照射上调原弹性蛋白和原纤维蛋白的合成真皮成纤维细胞从而促进日光性弹性组织变性的发展， 3) 确定角质形成细胞或成纤维细胞吸收的 UVR 是否会诱导真皮成纤维细胞合成弹性蛋白原和原纤维蛋白。具体将使用一代缺陷的小鼠品系来实现目标中性粒细胞产生 ROS，或中性粒细胞弹性蛋白酶释放不足或α-1蛋白酶抑制剂。弹性蛋白酶抑制剂也将用于体内。使用在合同条件下生长的人真皮成纤维细胞进行体外实验胶原凝胶或皮肤等同物将用于定义机制体内观察到的现象。