Platelet Activating Factor and Epidermal Cytotoxicity

描述（由申请人提供）：目前还不清楚各种刺激导致角质形成细胞细胞因子产生和细胞毒性的信号和过程。此外，由诸如紫外线辐射的试剂的慢性刺激导致恶性肿瘤。最近的研究表明，紫外线B辐射（UVB）损伤人角质形成细胞（HK）的部分原因是诱导氧化应激和细胞因子的产生。对角质形成细胞的严重UVB损伤也可导致细胞凋亡或程序性细胞死亡。我们小组和其他人的先前研究已经表明，角质形成细胞损伤，特别是通过导致氧化应激的试剂导致甘油磷酸胆碱（GPC）的产生，其可以作为血小板活化因子（PAF）或过氧化物酶体增殖物激活受体γ（PPAR 3）系统的激动剂。这项正在进行的研究应用的长期目标是阐明这些氧化的GPCs在急性UVB诱导的光响应中的作用。三个具体的目的是为了测试的假设，UVB介导的氧化损伤角质形成细胞的结果在生产新的ox-GPCs激活的PAF-R和PPAR 3系统。这些新的脂质增加细胞因子的产生，调节细胞凋亡，并诱导角质形成细胞增殖：1）。这些ox-GPC对急性UVB介导的炎症、细胞因子产生、DNA损伤/凋亡和增殖的作用将在PAF-R和表皮PPAR 3缺陷的小鼠中评估; 2）质谱方法将用于结构表征响应UVB产生的ox-GPC;和3）这些ox-GPC在人类急性UVB光响应中的作用将被确定。我们预计，这些研究使用新的体外和体内模型系统和新的方法，将导致在急性UVB诱导的角质形成细胞的细胞因子的产生，细胞毒性和增殖与PAF-R-和PPAR 3-激动作用的ox-GPCs的表征。这些信息将有助于了解氧化应激可能参与皮肤病理生理学的机制。由于这些介质将产生在其他器官系统的氧化应激反应，这些研究应该提供重要的见解和工具，研究ox-GPCs在人类病理生理学的影响。公共卫生相关性：紫外线B辐射（UVB）对角质形成细胞产生深远的影响，并导致大多数皮肤癌。我们小组最近的研究表明，UVB诱导甘油磷酸胆碱（GPC）的产生，可以作为血小板活化因子（PAF）或过氧化物酶体增殖物激活受体γ（PPAR 3）系统的激动剂。拟议的研究将确定的结构，并定义这些新的脂质介质在急性UVB光响应的作用。

DESCRIPTION (provided by applicant): The signals and processes by which diverse stimuli lead to keratinocyte cytokine production and cytotoxicity are presently not well understood. Moreover, chronic stimulation by agents such as ultraviolet radiation leads to malignancy. Recent studies have demonstrated that ultraviolet B radiation (UVB) damages human keratinocytes (HK) in part by inducing oxidative stress and cytokine production. Severe UVB damage to the keratinocyte can also result in apoptosis, or programmed cell death. Previous studies by our group and others have indicated that keratinocyte damage, especially via agents that result in oxidative stress results in the production of glycerophosphocholines (GPC) that can act as agonists for the Platelet-activating Factor (PAF) or the peroxisome proliferator activated receptor gamma (PPAR3) systems. The long-term objective of this ongoing research application is to elucidate the role of these oxidized GPCs in the acute UVB-induced photoresponse. Three specific aims are designed to test the hypothesis that UVB-mediated oxidative damage to the keratinocyte results in the production of novel ox-GPCs that activate the PAF-R and PPAR3 systems. These novel lipids augment cytokine production, modulate apoptosis, and induce keratinocyte proliferation: 1). The effect of these ox-GPCs on acute UVB-mediated inflammation, cytokine production, DNA damage/apoptosis and proliferation will be assessed in mice deficient in PAF-R and epidermal PPAR3; 2) Mass spectrometric methodologies will be used to structurally characterize ox-GPCs produced in response to UVB; and 3) The role of these ox-GPCs in the acute UVB photoresponse in humans will be determined. We anticipate that these studies using novel in vitro and in vivo model systems and novel methodologies will result in the characterization of ox-GPCs with PAF-R- and PPAR3- agonistic effects in acute UVB-induced keratinocyte cytokine production, cytotoxicity, and proliferation. This information will aid in the understanding of the mechanism(s) by which oxidative stress can be involved in cutaneous pathophysiology. Since these mediators would be produced in response to oxidative stress in other organ systems, these studies should provide important insights into and tools to study the impact of ox-GPCs in human pathophysiology. PUBLIC HEALTH RELEVANCE: Ultraviolet B radiation (UVB) induces profound effects upon keratinocytes and is responsible for the majority of skin cancers. Recent studies by our group have demonstrated that UVB induces the production of glycerophosphocholines (GPC) that can act as agonists for the Platelet-activating Factor (PAF) or the peroxisome proliferator activated receptor gamma (PPAR3) systems. The proposed studies will determine the structures of, and define the role of these novel lipid mediators in the acute UVB photoresponse.