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: 8403946
• 负责人: SANTOSH KUMAR KATIYAR
• 金额: $ 31.18万
• 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/8403946
• 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.

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.）中提取的植物化学物质）改善紫外线（UV）辐射引起的免疫抑制和 DNA 损伤的机制； (2) 确定这些机制对水飞蓟素介导的皮肤癌预防的贡献。紫外线引起的环丁烷嘧啶二聚体 (CPD) 形式的 DNA 损伤和免疫抑制已被证明与皮肤癌风险增加有关。我们已经证明，在体内小鼠模型中，水飞蓟素的局部治疗可以显着防止紫外线诱导的免疫抑制和致癌作用。众所周知，紫外线照射会损害树突状细胞和效应 T 细胞的功能，但会诱导抑制 T 细胞。此外，紫外线诱导的 DNA 损伤（主要是 CPD 的形成）是紫外线介导的免疫抑制的重要分子触发因素。我们已经证明，水飞蓟素能够增强暴露于紫外线的皮肤中 CPD+ 细胞的去除或修复，并抑制 UVB 诱导的小鼠接触超敏反应的抑制。我们的初步数据进一步表明，水飞蓟素可以增强暴露于紫外线的树突状细胞中 CPD 的去除，并恢复树突状细胞介导的活性，包括刺激 T 细胞。然而，水飞蓟素介导的紫外线诱导的免疫抑制作用在 DNA 修复缺陷的小鼠中被消除。总的来说，这些数据表明水飞蓟素抑制紫外线诱导的免疫抑制的能力与其预防光致癌的能力之间的关键联系。我们的假设是，水飞蓟素修复 UVB 诱导的 DNA 损伤对于其对紫外线诱导的免疫抑制和光致癌作用的化学预防作用至关重要。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紫外线诱导的耐受性树突状细胞的发育； (2) 确定水飞蓟素是否通过增强 T 细胞活化来抑制紫外线诱导的免疫抑制， (3) 确定水飞蓟素是否抑制紫外线诱导的调节性 T 细胞的发育； (4)确定水飞蓟素对光致癌作用的抑制是否是通过DNA修复介导的。拟议的研究应确定水飞蓟素纠正光致癌过程中紫外线诱导的免疫抑制的机制。我们解决了一个重大的公共卫生问题，因为人类皮肤过度暴露于太阳紫外线辐射是美国发生黑色素瘤和非黑色素瘤皮肤癌的主要病因。使用水飞蓟素开发新策略可能有助于降低人类患皮肤癌的风险。