Prevention of UV-carcinogenesis through DNA repair-dependent immunomodulation

通过 DNA 修复依赖性免疫调节预防紫外线致癌

• 批准号: 8210888
• 负责人: SANTOSH KUMAR KATIYAR
• 金额: $ 33.17万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210888
• 关键词: Accounting; Address; Adverse effects; Affect; Age; Animal Model; Antigens; Artichoke; Bone Marrow Transplantation; Caucasians; Caucasoid Race; Cells; Chemopreventive Agent; Chronic; Contact hypersensitivity; Cosmetics; Cutaneous Melanoma; DNA Damage; DNA Repair; Data; Defect; Dendritic Cells; Development; Devices; Effector Cell; Environment; Equilibrium; Excision; Expenditure; Exposure to; Family; Flavonoids; Generations; Genetic; Goals; Haptens; Healthcare; Human; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Inflammation Mediators; Interferons; Interleukin-10; Interleukin-12; Interleukin-4; Interleukin-5; Knowledge; Langerhans cell; Lead; Link; Malignant Neoplasms; Mediating; Milk Thistle; Molecular; Mus; Nucleotide Excision Repair; Ozone; Phytochemical; Plants; Population; Prevention; Preventive; Production; Public Health; Pyrimidine Dimers; Regulatory T-Lymphocyte; Risk; Silymarin; Skin; Skin Cancer; Skin Carcinoma; Skin Neoplasms; Skin Tissue; Skin tanning; Squamous cell carcinoma; Suppressor-Effector T-Lymphocytes; Surface; T-Cell Activation; T-Lymphocyte; Testing; Th2 Cells; The Sun; UV Radiation Exposure; UV induced; UVB induced; Ultraviolet Rays; United States; base; carcinogenesis; cytokine; immunoregulation; improved; in vivo; insight; member; mouse model; novel; prevent; public health relevance; repaired; research study; response; restoration; skin cancer prevention; tumor; ultraviolet; ultraviolet irradiation

DESCRIPTION (provided by applicant): The goals of the proposed studies are to: (1) Identify the mechanisms by which silymarin, a phytochemical obtained from milk thistle (Silybum marianum L.), ameliorates ultraviolet (UV) radiation-induced immunosuppression and DNA damage; and (2) Determine the contribution of these mechanisms to silymarin-mediated prevention of skin cancer. Both UV-induced DNA damage, in the form of cyclobutane pyrimidine dimers (CPDs), and immune suppression have been shown to be associated with an increased risk of skin cancer. We have demonstrated that topical treatment with silymarin provides significant protection against both UV-induced immunosuppression and carcinogenesis in an in vivo mouse model. UV irradiation is known to impair the function of dendritic cells and effector T cells but induce suppressor T cells. Furthermore, UV-induced DNA damage, predominantly the formation of CPDs, is an important molecular trigger for UV-mediated immunosuppression. We have demonstrated that silymarin has the ability to enhance the removal or repair of CPD+ cells in UV-exposed skin, and inhibits UVB-induced suppression of the contact hypersensitivity response in mice. Our preliminary data further indicate that silymarin can enhance the removal of CPDs in UV-exposed dendritic cells and restore dendritic cell-mediated activities including stimulation of T cells. However, silymarin mediated inhibition of UV-induced immunosuppression is abolished in mice that have defect in DNA repair. Collectively, these data implicate key links between the ability of silymarin to inhibit UV-induced immunosuppression and its ability to prevent photocarcinogenesis. Our hypothesis is that the repair of UVB-induced DNA damage by silymarin is critical for its chemopreventive effects on UV-induced immunosuppression and photocarcinogenesis. We propose four inter-related Specific Aims in which we will use genetically modified mouse model, including nucleotide excision repair-deficient mice: (1) Determine whether silymarin inhibits the development of UV-induced tolerogenic dendritic cells through restoration of dendritic cell activity; (2) Determine whether silymarin- induced inhibition of UV-induced immunosuppression occurs through enhancement of T-cell activation, (3) Determine whether silymarin inhibits the development of UV-induced regulatory T cells; and (4) Determine whether silymarin inhibition of photocarcinogenesis is mediated through DNA repair. The proposed studies should identify the mechanisms by which silymarin acts to correct UV-induced immunosuppression in photocarcinogenesis. We address a major public health concern as overexposure of the human skin to solar UV radiation is the major etiologic factor for the development of melanoma and non-melanoma skin cancers in the United States. The development of new strategies using silymarin may help to reduce the risk of skin cancer in humans. PUBLIC HEALTH RELEVANCE: Chronic exposure of the skin to solar ultraviolet (UV) radiation induces multiple adverse effects including the risk of skin cancer development. In vitro and in vivo studies have indicated that silymarin, a plant flavonoid obtained from milk thistle, possesses potent anti-photocarcinogenic activity. In the current application, we will determine the molecular mechanism of prevention of photocarcinogenesis by silymarin. This study will also highlight that rapid repair of UVB-induced DNA damage by silymarin will result in the enhancement or restoration of immune system and that will lead to the prevention of UV-carcinogenesis. The generation of new knowledge will provide novel insights into the mechanisms by which silymarin can either correct, or compensate for, the UV-induced damage that triggers or promotes photocarcinogenesis.

描述（由申请人提供）：拟议研究的目标是：（1）确定水飞蓟素，一种从水飞蓟（Silybum marianum L.）中获得的植物化学物质，改善紫外线（UV）辐射诱导的免疫抑制和DNA损伤;（2）确定这些机制对水飞蓟素介导的皮肤癌预防的贡献。紫外线诱导的DNA损伤，以环丁烷嘧啶二聚体（CPD）的形式，和免疫抑制已被证明与皮肤癌的风险增加有关。我们已经证明，局部治疗与水飞蓟素提供了显着的保护，对紫外线诱导的免疫抑制和致癌作用在体内小鼠模型。已知UV照射损害树突状细胞和效应T细胞的功能，但诱导抑制性T细胞。此外，UV诱导的DNA损伤，主要是CPD的形成，是UV介导的免疫抑制的重要分子触发剂。我们已经证明，水飞蓟素有能力提高去除或修复CPD+细胞在紫外线暴露的皮肤，并抑制UVB诱导的小鼠接触性超敏反应的抑制。我们的初步数据进一步表明，水飞蓟素可以增强紫外线暴露的树突状细胞中CPD的去除，并恢复树突状细胞介导的活动，包括刺激T细胞。然而，在DNA修复缺陷的小鼠中，水飞蓟素介导的对紫外线诱导的免疫抑制的抑制作用被消除。总的来说，这些数据暗示了水飞蓟素抑制紫外线诱导的免疫抑制的能力和其防止光致癌作用的能力之间的关键联系。我们的假设是，修复UVB诱导的DNA损伤的水飞蓟素是至关重要的紫外线诱导的免疫抑制和光致癌的化学预防作用。我们提出了四个相互关联的具体目标，其中我们将使用转基因小鼠模型，包括核苷酸切除修复缺陷小鼠：（1）确定水飞蓟素是否通过恢复树突状细胞活性来抑制UV诱导的耐受性树突状细胞的发育;（2）确定水飞蓟素诱导的对UV诱导的免疫抑制的抑制是否通过增强T细胞活化而发生，（3）确定水飞蓟素是否抑制UV诱导的调节性T细胞的发育;和（4）确定水飞蓟素对光致癌作用的抑制是否通过DNA修复介导。拟议的研究应确定的机制，水飞蓟素的行为，以纠正紫外线诱导的免疫抑制在光致癌作用。我们解决了一个主要的公共卫生问题，因为人类皮肤过度暴露于太阳紫外线辐射是美国黑色素瘤和非黑色素瘤皮肤癌发展的主要病因因素。使用水飞蓟素的新策略的开发可能有助于降低人类皮肤癌的风险。 公共卫生相关性：皮肤长期暴露于太阳紫外线（UV）辐射会引起多种不良影响，包括患皮肤癌的风险。体外和体内研究表明，水飞蓟素是一种从水飞蓟中提取的黄酮类化合物，具有很强的抗光致癌活性。在当前的应用中，我们将确定水飞蓟素预防光致癌作用的分子机制。本研究还将强调，快速修复UVB诱导的DNA损伤的水飞蓟素将导致增强或恢复免疫系统，这将导致预防紫外线致癌。新知识的产生将为水飞蓟素纠正或补偿引发或促进光致癌作用的UV诱导损伤的机制提供新的见解。