Oxidized Lipids and UV Immunosuppression

氧化脂质和紫外线免疫抑制

• 批准号: 10010381
• 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/10010381
• 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/antagonist; 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）辐射对皮肤有深远的影响，并产生发热的全身性后果 到免疫抑制到维生素D的产生。UVB既能作为免疫抑制剂， 诱变剂允许这种环境因子作为一种完全的致癌物，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高的地区，预计紫外线指数将增加。因此，在本发明中， 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 当紫外线穿透表皮时，光生物学中的一个主要问题是紫外线处理过的皮肤如何发送系统信号。 最近的研究表明，小的膜结合囊泡称为微泡颗粒（MVP） 细胞对各种应激源的反应中释放出的蛋白质可以作为有效的信号传导剂， 细胞核和细胞质成分。我们已经证明，UVB产生MVP从上皮细胞释放， 细胞和皮肤，这可能提供了一个潜在的机制UVB介导的系统信号。本集团与 其他人先前报道UVB辐射产生高水平的脂质介质血小板活化 酶促产生的PAF因子（PAF）和非酶促产生的PAF受体（PAFR）激动剂， 活性氧物质。最近使用抗氧化剂和PAFR表达/无效细胞系的研究， 酸性鞘磷脂酶（aSMase）的药理学/遗传学抑制与 在UVB产生的MVP（UVB-MVP）中，PAFR信号传导导致aSM酶活化。最后，我们提供 证据表明，UVB-MVP携带生物活性PAF激动剂，我们假设介导延迟的 UVB的免疫抑制作用。然而，关于UVB-MVP是如何产生的，以及如果 可以利用新的途径来解决UVB诱导的皮肤肿瘤免疫抑制 生成/进展。计划对这一长期运行和高生产率的VA进行更新， 优异奖，围绕氧化甘油磷酸胆碱在紫外线诱导的 免疫抑制这些目的旨在测试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转移局部和全身效应 激动剂目的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。目标2将使用工具（在目标1中得到部分验证）来定义UVB的作用- MVP在UVB的延迟免疫抑制和肿瘤促进作用中的作用。成功完成该项目 将（i）解决光生物学中的一个重要问题，即角质细胞特异性刺激如何产生 系统信号作用，（ii）提供阻断UVB局部和系统作用的药理学机制。