Oxidized lipids and UV immunosuppression

描述(由申请人提供)： 项目摘要：我们研究的主要目标是对紫外线B辐射(UVB)引起的全身性免疫抑制进行力学表征。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辐射疗法在临床上用于治疗炎症性皮肤病，这在很大程度上是因为它的免疫抑制作用。计划中的研究计划利用我们实验室和其他研究的结果，这些研究表明，UVB介导的全身免疫抑制涉及表皮细胞对UVB的反应产生的新型甘油磷胆碱衍生的脂类。这些化合物，其中一些还没有结构特征，作为血小板激活因子(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产生的二十烷类化合物、白细胞介素10和组胺)的复杂相互作用而发挥免疫抑制作用。计划有两个特定的目标，利用一个公认的接触性超敏反应小鼠模型，从机械上表征UVB介导的全身免疫抑制的复杂途径。第一个目标是使用质谱仪对紫外线在小鼠皮肤中产生的PAF-R激动剂进行结构表征和定量。这些新的PAF-R配体的数量以及通过非酶自由基介导的甘油磷酸胆碱氧化产生的数量将使用PAF酶合成缺陷的小鼠和系统性抗氧化剂的使用进行评估。第二个目标将通过新的小鼠移植研究来表征肥大细胞和调节性T细胞的作用。完成计划中的研究，以确定UVB介导的全身免疫抑制所涉及的细胞类型和介质，应该会增强对这一与皮肤癌密切相关的重要过程的理解。 公共卫生相关性： 项目简介：我们研究的主要目标是从机制上描述紫外线B辐射(UVB)介导的全身免疫抑制所涉及的细胞类型和介体。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。这些皮肤癌和癌前光化性角化病是退伍军人中发现的最常见的肿瘤性疾病。尽管光化性肿瘤通常与死亡率增加无关，但它构成了卫生保健资源的巨大负担和发病率的增加。此外，UVB辐射治疗在临床上用于治疗炎症性皮肤病，很大程度上是因为它的免疫抑制作用。这些研究应有助于加深对这一重要进程的理解。

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.