Oxidized Lipids and UV Immunosuppression

氧化脂质和紫外线免疫抑制

• 批准号: 10293535
• 负责人: Jeffrey B. Travers
• 金额: --
• 依托单位: DAYTON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293535
• 关键词: Actinic keratosis; Address; Agonist; Antioxidants; Area; Carcinogens; Cell Line; Cells; Chemotherapy and/or radiation; Cigarette; Clinic; Data; Dermatology; Diagnosis; Dose; Enzyme Inhibition; Enzymes; Epidermis; Epithelial Cells; Event; Fever; Financial Hardship; Generations; Genetic; Goals; Grant; Healthcare Systems; Human; Immune response; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Individual; Ions; Knock-out; Knockout Mice; Knowledge; Laboratories; Link; Malignant - descriptor; Mediating; Membrane; Metabolic; Military Personnel; Modeling; Morbidity - disease rate; Mus; Mutagens; Neoplasms; Nuclear; Null Lymphocytes; Outcome; Oxides; PUVA Photochemotherapy; Pathway interactions; Pharmacology; Photobiology; Photosensitivity; Physiological; Platelet Activating Factor; Play; Process; Production; Radiation therapy; Reaction; Reactive Oxygen Species; Receptor Signaling; Reporting; Research; Role; Running; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Skin; Skin Cancer; Skin Carcinoma; Skin Neoplasms; Source; Stimulus; Testing; Transfer Factor; UV Radiation Exposure; UV induced; UV response; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Vesicle; Veterans; Vitamin D; Work; XPA gene; acid sphingomyelinase; design; environmental agent; environmental stressor; genetic approach; in vivo; indexing; inhibitor; keratinocyte; lipid mediator; mast cell; melanoma; microvesicles; military veteran; neoplastic cell; novel; oxidized lipid; particle; platelet activating factor receptor; premalignant; response; stressor; tool; tumor; tumor progression; ultraviolet

PROJECT SUMMARY Ultraviolet B (UVB) radiation has profound effects upon skin and generates systemic consequences from fever to immunosuppression to vitamin D production. The ability of UVB to serve as both an immunosuppressant and mutagen allows this environmental agent to serve as a complete carcinogen, and is the cause for non-melanoma skin cancer and melanoma. Skin cancer is the most common diagnosis in VA Dermatology clinics, and this is expected to increase as our military forces are often stationed in areas with a high UV index. Thus, understanding the mechanisms by which UVB generates skin cancer is relevant to our veterans. As UVB only penetrates the epidermis, a major question in photobiology is how UVB-treated skin sends systemic signals. Recent studies have indicated that small membrane-bound vesicles known as microvesicle particles (MVP) released from cells in response to various stressors can act as potent signaling agents due to their ability to carry nuclear and cytoplasmic components. We have demonstrated that UVB generates MVP release from epithelial cells and skin, which could provide a potential mechanism for UVB-mediated systemic signaling. Our group and others have previously reported that UVB radiation generates high levels of the lipid mediator Platelet-activating factor (PAF) produced enzymatically and PAF-receptor (PAFR) agonists produced non-enzymatically via reactive oxygen species. Recent studies using antioxidants and PAFR-expressing/null cell lines and pharmacologic/genetic inhibition of the enzyme acid sphingomyelinase (aSMase) have implicated involvement of PAFR signaling resulting in aSMase activation in UVB generated MVP (UVB-MVP). Finally, we provide evidence that UVB-MVP carry bioactive PAF agonists, which we hypothesize mediate the delayed immunosuppressive effects of UVB. Yet knowledge gaps exist as to how UVB-MVP are generated and if this new pathway can be exploited to address UVB-induced immunosuppression involved in skin tumor generation/progression. Two aims are planned for the renewal of this long-running and highly productive VA Merit grant which is centered around the role of oxidized glycerophosphocholines in UV-induced immunosuppression. These aims are designed to test the hypothesis that UVB generates MVP in human skin in a PAF-dependent manner involving aSMase and transfers both local and systemic effects via their carried PAF agonists. Aim 1 will use in vitro cell lines and murine genetic and pharmacologic models to determine the mechanisms of UVB-MVP generation. Aim 2 will use tools (in part validated in Aim 1) to define the roles of UVB- MVP in delayed immunosuppressive and tumor-promoting effects of UVB. Successful completion of this project will (i) address an important question in photobiology as to how a keratinocyte-specific stimulus can generate systemic signaling effects, (ii) offer pharmacologic mechanisms to block UVB local and systemic effects.

项目总结 紫外线B(UVB)辐射对皮肤有深远的影响，并会因发烧而产生全身后果 从免疫抑制到维生素D的产生。中波紫外线既能作为免疫抑制剂，又能发挥免疫抑制作用 诱变剂允许这种环境因素作为一种完全的致癌物，是非黑色素瘤的原因。 皮肤癌和黑色素瘤。皮肤癌是退伍军人事务部皮肤科诊所最常见的诊断，这是 预计会增加，因为我们的军事力量经常驻扎在紫外线指数较高的地区。因此， 了解UVB引发皮肤癌的机制对我们的老兵来说是相关的。仅作为UVB 穿透表皮，光生物学的一个主要问题是UVB治疗的皮肤如何发出全身信号。 最近的研究表明，与膜结合的小泡称为微泡颗粒(MVP)。 细胞对各种应激源的反应所释放的物质可以作为有效的信号媒介，这是因为它们能够携带 核质成分。我们已经证明UVB从上皮细胞产生MVP释放 细胞和皮肤，这可能为UVB介导的全身信号提供一种潜在的机制。我们的团队和 其他人此前曾报道，UVB辐射会产生高水平的脂质介质--血小板激活 因子(PAF)和PAF受体(PAFR)激动剂通过非酶途径产生 活性氧物种。最近使用抗氧化剂和PAFR表达/空细胞系和 酸性鞘磷脂酶(ASMase)的药理/遗传抑制与此有关 在UVB产生的MVP(UVB-MVP)中，PAFR信号导致aSMase激活。最后，我们提供 UVB-MVP携带生物活性PAF激动剂的证据，我们假设这些激动剂介导了迟发性 中波紫外线的免疫抑制作用。然而，关于UVB-MVP是如何产生的以及如果这一点 可以开发新的途径来解决UVB诱导的与皮肤肿瘤有关的免疫抑制 世代/进步。为更新这一长期运行和高生产率的退伍军人管理局，计划实现两个目标 以氧化甘油磷胆碱在紫外线诱导中的作用为中心的功绩补助 免疫抑制。这些目的是为了测试UVB在人体皮肤中产生MVP的假设 一种涉及aSMase的PAF依赖方式，并通过其携带的PAF传递局部和全身效应 激动剂。AIM 1将使用体外细胞系和小鼠遗传和药理学模型来确定 UVB-MVP的产生机制。AIM 2将使用工具(在AIM 1中部分验证)来定义UVB的角色- MVP在中波紫外线迟发性免疫抑制和促肿瘤作用中的作用本项目圆满完成 我将解决光生物学中的一个重要问题，即角质形成细胞特异性刺激是如何产生的 系统信号效应，(Ii)提供阻断UVB局部和全身效应的药理机制。