Oxidized Lipids and UV Immunosuppression

氧化脂质和紫外线免疫抑制

• 批准号: 10514568
• 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/10514568
• 关键词: Actinic keratosis; Address; Agonist; Antioxidants; Area; Binding; Carcinogens; Cell Line; Cells; Clinic; Cytoplasm; 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; Ionizing radiation; Knock-out; Knockout Mice; Knowledge; Laboratories; Link; Mediating; Membrane; Metabolic; Military Personnel; Modeling; Morbidity - disease rate; Mus; Mutagens; Neoplasms; Nuclear; Null Lymphocytes; Outcome; PUVA Photochemotherapy; Pathway interactions; Penetration; Photobiology; Physiological; Platelet Activating Factor; Play; Process; Production; Productivity; Radiation therapy; Reaction; Reactive Oxygen Species; Receptor Signaling; Regulatory T-Lymphocyte; Reporting; Research; Role; Running; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Skin; Skin Cancer; Skin Carcinoma; Skin Neoplasms; Source; Stimulus; Testing; Transfer Factor; Tumor Promotion; UV Radiation Exposure; UV induced; UV response; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Vesicle; Veterans; Vitamin D; Work; XPA gene; acid sphingomyelinase; chemotherapy; cigarette smoke; 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; pharmacologic; platelet activating factor receptor; premalignant; response; stressor; tool; 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.

项目概要 紫外线 B (UVB) 辐射对皮肤有深远影响，并会因发烧而产生全身性后果 免疫抑制影响维生素 D 的产生。 UVB 既可以作为免疫抑制剂， 诱变剂使这种环境因素完全致癌，并且是非黑色素瘤的原因 皮肤癌和黑色素瘤。皮肤癌是 VA 皮肤科诊所最常见的诊断，这是 由于我们的军队经常驻扎在紫外线指数较高的地区，预计这一数字还会增加。因此， 了解 UVB 产生皮肤癌的机制与我们的退伍军人息息相关。仅作为 UVB 穿透表皮，光生物学的一个主要问题是经过 UVB 处理的皮肤如何发送系统信号。 最近的研究表明，称为微泡颗粒（MVP）的小膜结合囊泡 细胞响应各种压力而释放的信号分子可以作为有效的信号剂，因为它们能够携带 核和细胞质成分。我们已经证明 UVB 可以从上皮细胞中释放 MVP 细胞和皮肤，这可以为 UVB 介导的系统信号传导提供潜在机制。我们组和 其他人之前曾报道过 UVB 辐射会产生高水平的脂质介质血小板激活剂 酶促因子 (PAF) 和非酶促 PAF 受体 (PAFR) 激动剂通过 活性氧。最近的研究使用抗氧化剂和 PAFR 表达/无效细胞系和 酸性鞘磷脂酶 (aSMase) 的药理学/遗传抑制可能涉及其中 PAFR 信号传导导致 UVB 生成 MVP (UVB-MVP) 中 aSMase 激活。最后，我们提供 有证据表明 UVB-MVP 携带生物活性 PAF 激动剂，我们假设它介导了延迟 UVB 的免疫抑制作用。然而，对于 UVB-MVP 是如何产生的以及是否会产生这种情况，仍存在知识差距。 新途径可用于解决皮肤肿瘤中 UVB 诱导的免疫抑制问题 世代/进展。这个长期运行且高效的 VA 的更新计划有两个目标 优异奖的重点是氧化甘油磷酸胆碱在紫外线诱导中的作用 免疫抑制。这些目标旨在检验 UVB 在人体皮肤中产生 MVP 的假设 涉及 aSMase 的 PAF 依赖性方式，并通过其携带的 PAF 传递局部和全身效应 激动剂。目标 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 生成机制。目标 2 将使用工具（在目标 1 中部分验证）来定义 UVB 的角色 UVB 延迟免疫抑制和肿瘤促进作用的 MVP。本项目顺利完成 将（i）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如何产生 系统信号效应，(ii) 提供阻断 UVB 局部和全身效应的药理学机制。