MECHANISMS FOR CHRONIC UVR INDUCED DAMAGE TO SKIN

描述：(改编自申请人的摘要)-长期 这项研究的目的是阐明导致脑出血的机制。 皮肤因暴露在太阳紫外线下而发生的皮肤重塑 辐射(UVR)多年，希望制定策略来 抑制这些组织改变。与年龄有关的皮肤变化(光老化 和内在衰老)导致临床上重要的生理变化 对老年人来说是一个严重的医疗问题。所采取的方法 这项提议是为了调查由 有三种细胞类型，角质形成细胞、肥大细胞和中性粒细胞 光老化皮肤的发育，特别是在合成增加方面 原弹性蛋白和糖胺多聚糖(GAG)。 第一个具体目标是确定皮肤是否长期暴露于 UVR诱导表皮细胞产生介体， 皮肤光老化。这将通过以下方式实现：a)确定是否 表皮是吸收紫外线辐射的主要场所。 弹性蛋白、GAG、组织学和原弹性蛋白mRNA的稳态变化 级别。B)评估角质形成细胞上清液的能力 体外暴露于UVR刺激成纤维细胞合成 原弹性蛋白和GAG，并增加原弹性蛋白稳定状态的mRNA水平。 将对可能的UVR诱导的调解器进行评估。第二个具体目标 就是确定肥大细胞产物是否是 皮肤光老化的机制。这将通过以下方式实现：a) 慢性紫外线照射产生的弹性蛋白、GAG和组织学的比较 肥大细胞缺陷小鼠和正常小鼠。B)确定真皮 成纤维细胞增加其合成活性以响应肥大细胞 使用激活的和脱颗粒的肥大细胞的混合物进行体外产物 和精选的肥大细胞产品。原弹性蛋白和原弹性蛋白的合成速率 GAG和原弹性蛋白的信使核糖核酸水平将被测量。第三个具体问题 目的是检验中性粒细胞的产物是重要的这一假设。 真皮光老化机制中的介体。中性粒细胞 将使用弹性蛋白酶缺陷小鼠，并合成Gag，特征 将用来测量慢性紫外线的影响，通过 曝光。中性粒细胞产品将在体外进行测试，以确定它们是否能够 改变成纤维细胞的合成活性。

DESCRIPTION: (Adapted from the applicant's abstract) - The long-term objective of this research is to elucidate mechanisms responsible for the dermal remodeling that occurs in response to exposure of skin to solar UV radiation (UVR) over many years with the hope of devising strategies to inhibit these tissue alterations. Age-related changes in skin (photoaging and intrinsic aging) result in clinically important physiological changes and are a significant medical problem in the elderly. The approach taken in this proposal is to investigate the importance of mediators produced by three cell types, keratinocytes, mast cells, and neutrophils in the development of photoaged skin and particularly, in the increased synthesis of tropoelastin and glycosaminoglycans (GAGs). The first specific aim is to determine whether chronic exposure of skin to UVR induces production of mediators from epidermal cells that initiate dermal photoaging. This will be accomplished by: a) Determining whether the epidermis is the primary site for absorption of UVR that initiates changes in elastin, GAGs, histology and tropoelastin mRNA steady-state levels. b) Assessing the ability of supernatants from keratinocytes that are exposed to UVR in vitro to stimulate fibroblast synthesis of tropoelastin and GAGs and increase tropoelastin steady state mRNA levels. Possible UVR-induced mediators will be evaluated. The second specific aim is to determine whether mast cell products are important mediators in the mechanism for dermal photoaging. This will be accomplished by: a) Comparing the elastin, GAGs, and histology produced by chronic UVR exposure of mast cell-deficient mice and normal mice. b) Determining whether dermal fibroblasts increase their synthetic activity in response to mast cell products in vitro using mixtures from activated and degranulated mast cells and selected mast cell products. Rates of synthesis of tropoelasin and GAGs, and mRNA levels for tropoelastin will be measured. The third specific aim is to test the hypothesis that products of neutrophils are important mediators in the mechanism for dermal photoaging. Neutrophil elastase-deficient mice will be employed, and synthesis of GAGs, character of GAGs and histology will be used to measure the effects of chronic UV by exposure. Neutrophil products will be tested in vitro for their ability to alter fibroblast synthetic activity.