Oxidized lipids and UV immunosuppression

氧化脂质和紫外线免疫抑制

• 批准号: 7932683
• 负责人: Jeffrey B. Travers
• 金额: --
• 依托单位: RLR 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 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932683
• 关键词: Actinic keratosis; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Cancerous; Cells; Chronic; Clinical; Complex; Contact hypersensitivity; Disease; Eicosanoids; Environmental Risk Factor; Enzymes; Exposure to; Free Radicals; Goals; Healthcare; Histamine; Human; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammatory; Interleukin-10; Laboratories; Ligands; Lipids; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Mutagens; Neoplasms; Pathway interactions; Phototherapy; Platelet Activating Factor; Play; Process; Production; Property; Radiation; Reactive Oxygen Species; Regulatory T-Lymphocyte; Research; Resources; Role; Skin; Skin Cancer; Skin Carcinoma; Stimulus; Sun Exposure; Sunlight; Testing; Therapeutic Effect; Transplantation; Ultraviolet B Radiation; Veterans; cell type; cyclooxygenase 2; cytokine; design; in vivo; insight; keratinocyte; mast cell; mortality; neoplastic; novel; oxidation; oxidized lipid; platelet activating factor receptor; research study; response; skin disorder; stressor; tool; ultraviolet

DESCRIPTION (provided by applicant): PROJECT SUMMARY: The primary goal of our research is to mechanistically characterize systemic immunosuppression induced by ultraviolet B radiation (UVB). The immunosuppressive effects of UVB are involved in the ability of this environmental stimulus to induce skin cancers. Moreover, UVB radiation treatments are used clinically to treat inflammatory skin disorders, in great part to its immunosuppressive effects. The planned research plans to take advantage of results of previous studies both in our laboratory and others indicating that UVB-mediated systemic immunosuppression involves novel glycerophosphocholine-derived lipids produced by epidermal cells in response to UVB. These compounds, some of which have not been structurally characterized, act as agonists for the Platelet-activating Factor (PAF) receptor. Accumulating evidence suggests that these PAF-R agonists exert immunosuppressive effects via a complex interplay of cell types and cytokines including mast cells, cyclooxygenase-2-produced eicosanoids, interleukin-10 and histamine. Two specific aims are planned to mechanistically characterize the complex pathway of UVB-mediated systemic immunosuppression using a well-established murine model of contact hypersensitivity. The first aim will use mass spectrometry to structurally characterize and quantitate PAF-R agonists produced by UVB in murine skin. The amounts of these novel PAF-R ligands produced enzymatically as well as through non- enzymatic free radical-mediated oxidation of glycerophosphosphocholines will be assessed using a mouse defective in PAF enzymatic synthesis and use of systemic antioxidants. The second aim will characterize the roles of mast cells and regulatory T cells using novel murine transplantation studies. Completion of the planned studies to characterize the cell types and mediators involved in UVB-mediated systemic immunosuppression should result in an enhanced understanding of this important process intimately involved in skin cancer. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE: The primary goal of our research is to mechanistically characterize the cell types and mediators involved in ultraviolet B radiation (UVB)-mediated systemic immunosuppression. The immunosuppressive effects of UVB are involved in the ability of this environmental stimulus to induce skin cancers. These skin cancers and pre- cancerous actinic keratoses induced by chronic sun exposure are the most common form of neoplastic disorders found in veterans. Though usually not associated with increased mortality, actinic neoplasias constitute an enormous burden of health care resources and increased morbidity. Moreover, UVB radiation treatments are used clinically to treat inflammatory skin disorders, in great part to its immunosuppressive effects. These studies should result in an enhanced understanding of this important process.

描述（由申请人提供）： 项目摘要：我们研究的主要目标是从机制上表征紫外线 B 辐射 (UVB) 引起的系统性免疫抑制。 UVB 的免疫抑制作用与这种环境刺激诱发皮肤癌的能力有关。此外，UVB辐射治疗在临床上用于治疗炎症性皮肤病，很大程度上是由于其免疫抑制作用。 计划中的研究计划利用我们实验室和其他实验室之前的研究结果，表明 UVB 介导的系统性免疫抑制涉及表皮细胞响应 UVB 产生的新型甘油磷酸胆碱衍生脂质。这些化合物（其中一些尚未进行结构表征）充当血小板激活因子（PAF）受体的激动剂。越来越多的证据表明，这些 PAF-R 激动剂通过细胞类型和细胞因子（包括肥大细胞、环氧合酶 2 产生的类二十烷酸、白细胞介素 10 和组胺）之间复杂的相互作用发挥免疫抑制作用。 计划有两个具体目标，即使用完善的接触性超敏反应小鼠模型从机制上表征 UVB 介导的系统性免疫抑制的复杂途径。第一个目标是使用质谱法对小鼠皮肤中 UVB 产生的 PAF-R 激动剂进行结构表征和定量。将使用PAF酶促合成和全身抗氧化剂的使用有缺陷的小鼠来评估通过酶促以及通过非酶促自由基介导的甘油磷酸胆碱氧化产生的这些新型PAF-R配体的量。第二个目标将利用新型小鼠移植研究来表征肥大细胞和调节性 T 细胞的作用。完成计划的研究来表征 UVB 介导的全身免疫抑制中涉及的细胞类型和介质，应该会加深对与皮肤癌密切相关的这一重要过程的了解。 公共卫生相关性： 项目叙述：我们研究的主要目标是从机制上表征参与紫外线 B 辐射 (UVB) 介导的全身免疫抑制的细胞类型和介质。 UVB 的免疫抑制作用与这种环境刺激诱发皮肤癌的能力有关。这些由长期阳光照射引起的皮肤癌和癌前光化性角化病是退伍军人中最常见的肿瘤性疾病。尽管通常与死亡率增加无关，但光化性肿瘤构成了医疗保健资源的巨大负担并增加了发病率。此外，UVB辐射治疗在临床上用于治疗炎症性皮肤病，很大程度上是由于其免疫抑制作用。这些研究应该会加深对这一重要过程的理解。