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.

项目摘要 紫外线B（UVB）辐射对皮肤具有深远的影响，并产生发烧的全身后果 对维生素D产生的免疫抑制。 UVB既可以作为免疫抑制剂，又有能力 诱变剂允许该环境剂充当完整的致癌物，是非黑色素瘤的原因 皮肤癌和黑色素瘤。皮肤癌是VA皮肤科诊所中最常见的诊断，这是 随着我们的军队经常驻扎在紫外线指数高的地区，预计会增加。因此， 了解UVB产生皮肤癌的机制与我们的退伍军人有关。仅作为UVB 穿透表皮，光生物学的主要问题是UVB处理的皮肤如何发送全身信号。 最近的研究表明，膜结合的小囊泡称为微泡颗粒（MVP） 从细胞响应各种压力源的细胞释放可以充当有效的信号传导剂，因为它们的携带能力 核和细胞质成分。我们已经证明UVB从上皮生成MVP释放 细胞和皮肤，这可以为UVB介导的全身信号传导提供潜在的机制。我们的小组和 其他人先前已经报道说，UVB辐射会产生高水平的脂质介体血小板激活 因子（PAF）通过酶促和PAF受体（PAFR）激动剂通过非酶通过 活性氧。使用抗氧化剂和表达PAFR的/无效细胞系的最新研究以及 酶酸鞘磷脂酶（ASMase）的药理/遗传抑制已牵涉到参与 PAFR信号传导导致UVB生成的MVP（UVB-MVP）中的ASMase激活。最后，我们提供 UVB-MVP携带生物活性PAF激动剂的证据，我们假设该激动剂介导了延迟 UVB的免疫抑制作用。然而，知识差距存在如何生成UVB-MVP，如果这样 可以利用新途径来解决与皮肤肿瘤有关的UVB诱导的免疫抑制 产生/进展。计划续签这两个长期且高效的VA的目标 优点授予围绕氧化的甘油磷胆碱在紫外线诱导的 免疫抑制。这些目的旨在测试UVB在人类皮肤中产生MVP的假设 涉及ASMase的PAF依赖性方式，并通过其携带的PAF转移局部和全身效应 激动剂。 AIM 1将使用体外细胞系以及鼠遗传和药理模型来确定 UVB-MVP生成的机制。 AIM 2将使用工具（部分在AIM 1中验证）来定义UVB-的角色 UVB的延迟免疫抑制和肿瘤促进作用中的MVP。成功完成该项目 （i）将在光生物学中解决一个重要的问题，即如何产生角质形成细胞特异性刺激 全身信号传导效应，（ii）提供了药理机制，以阻止UVB局部和全身效应。