Prevention of photocarcinogenesis by dietary immunomodulation

通过饮食免疫调节预防光致癌

• 批准号: 8431273
• 负责人: SANTOSH KUMAR KATIYAR
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431273
• 关键词: Accounting; Address; Adverse effects; Affect; Afghanistan; Age; Animal Model; Antigens; Caring; Caucasians; Caucasoid Race; Cells; Chemopreventive Agent; Chronic; Cosmetics; Cutaneous; Cutaneous Melanoma; DNA Damage; DNA Repair; Data; Defect; Dendritic Cells; Development; Devices; Diet; Effector Cell; Equilibrium; Event; Excision; Exhibits; Exposure to; Family; Generations; Genetic; Goals; Gulf War; Haptens; Healthcare; Human; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Incidence; Interleukin-10; Interleukin-12; Iraq; Knowledge; Laboratory Animals; Langerhans cell; Lead; Malignant Neoplasms; Mediating; Molecular; Mus; Nucleotide Excision Repair; Ozone; Persian Gulf; Pilot Projects; Play; Population; Prevention; Preventive; Proanthocyanidins; Production; Public Health; Pyrimidine Dimers; Quality of life; Regulatory T-Lymphocyte; Risk; Risk Factors; Role; Series; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Skin Tissue; Skin tanning; Squamous cell carcinoma; Suppressor-Effector T-Lymphocytes; Surface; T-Cell Activation; T-Lymphocyte; Testing; Th2 Cells; The Sun; Toxic effect; UV Radiation Exposure; UV induced; UVB induced; Ultraviolet Rays; United States; Veterans; War; abstracting; base; carcinogenesis; cytokine; grape seed; immunoregulation; improved; in vivo; mouse model; novel; prevent; public health relevance; repaired; research study; response; restoration; skin cancer prevention; tumor; ultraviolet

DESCRIPTION (provided by applicant): Abstract Overexposure of the human skin to solar ultraviolet (UV) radiation is the major etiologic agent for the development of melanoma and non-melanoma skin cancers in the United States, with non-melanoma skin cancer being the most common cutaneous malignancy. We have demonstrated that dietary grape seed proanthocyanidins (GSPs) provide significant protection against UV-induced skin carcinogenesis in an in vivo mouse model and have further demonstrated that dietary GSPs provide significant protection against UV- induced immunosuppression, a well-established risk factor for skin cancer. The goal of the proposed studies is to establish the mechanisms by which dietary GSPs act to correct UV-induced immunosuppression associated with photocarcinogenesis by: (i) Identifying the mechanisms by which dietary GSPs ameliorate UV radiation- induced immunosuppression and DNA damage; and (ii) Determining the contribution of these mechanisms to GSPs-mediated prevention of skin cancer. Currently, it is known that UV-induced DNA damage in the form of generation of cyclobutane pyrimidine dimers (CPDs) is a risk factor for cancer and is an important molecular trigger for UV-mediated immunosuppression and that UV-mediated immunosuppression is associated with the induction of suppressor cells and impaired function of dendritic cells and effector T cells. The critical question is therefore whether the GSPs act on multiple fronts to prevent or correct UV-induced immunosuppression or act by blocking the early events that initiate immunosuppression. Our pilot studies suggest that GSPs have the ability to enhance the removal or repair of CPD+ cells in UV-exposed skin and our preliminary data further indicate that GSPs can act to enhance the removal of CPDs in UV-exposed dendritic cells and restore dendritic cell-mediated activities, including stimulation of T cells. Notably, dietary GSPs do not inhibit UV-induced immunosuppression in those mice which have a defect in DNA repair. Together, these data suggest the hypothesis that the repair of UVB-induced DNA damage by GSPs in dendritic cells is critical for their 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 dietary GSPs inhibit the development of UV-induced tolerogenic dendritic cells through restoration of dendritic cell activity; (2) Determine whether dietary GSPs inhibit UV-induced immunosuppression through enhancement of T-cell activation, (3) Determine whether dietary GSPs inhibit the development of UV-induced regulatory T cells; and (4) Determine whether inhibition of photocarcinogenesis by dietary GSPs is mediated through DNA repair. SIGNIFICANCE: These studies address a major public health and VA healthcare concern, i.e., the growing incidence of skin cancers. The development of more effective preventive approaches, such as dietary GSPs that exhibit no toxicity in mice, requires an improved understanding of the mechanisms by which they prevent UVB-induced carcinogenesis.

描述（由申请人提供）： 在美国，人皮肤上的皮肤过度暴露于太阳能紫外线（UV）辐射是发展黑色素瘤和非黑色素瘤皮肤癌的主要病因剂，非黑色素瘤皮肤癌是最常见的皮肤恶性肿瘤。我们已经证明，在体内小鼠模型中，饮食中的葡萄种子原动蛋白（GSP）为紫外线诱导的皮肤致癌作用提供了明显的保护，并进一步证明，饮食中的GSP可为紫外线诱导的免疫抑制提供明显的保护，这是对皮肤癌的良好危险因素。拟议的研究的目的是建立饮食GSP的机制，通过以下方式纠正与光核生成相关的紫外线诱导的免疫抑制的机制：（i）确定饮食中饮食中的饮食GSPS可以改善紫外线辐射诱导的免疫抑制作用和DNA损伤的机制； （ii）确定这些机制对GSPS介导的皮肤癌的预防的贡献。 目前，众所周知，紫外丁烷嘧啶二聚体（CPDS）的形式是紫外线诱导的DNA损伤，是癌症的危险因素，是紫外线介导的免疫抑制作用的重要分子触发因素，并且uv介导的uv介导的免疫抑制与抑制细胞和受损害细胞的诱导相关。因此，关键的问题是GSP是在多个方面起作用以防止或纠正紫外线诱导的免疫抑制作用还是通过阻止引发免疫抑制的早期事件来起作用。我们的试点研究表明，GSP具有增强紫外线暴露皮肤中CPD+细胞的去除或修复的能力，我们的初步数据进一步表明，GSP可以提高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性，包括T细胞的刺激。值得注意的是，饮食GSP不会抑制那些在DNA修复缺陷的小鼠中紫外线诱导的免疫抑制。总之，这些数据表明假设在树突状细胞中GSP对UVB诱导的DNA损伤的修复对于它们对紫外线诱导的免疫抑制和光carcinogenogeny的化学预防作用至关重要。我们提出了四个相互关联的特定目的，其中我们将使用遗传修饰的小鼠模型，包括核苷酸切除修复缺陷型小鼠：（1）确定饮食中的GSP是否通过恢复树突状细胞活性来抑制饮食中的饮食GSP的发展； （2）确定饮食GSP是否通过增强T细胞激活抑制了紫外线诱导的免疫抑制，（3）确定饮食GSP是否抑制了紫外线诱导的调节性T细胞的发展； （4）确定是否通过DNA修复介导了通过饮食GSP抑制光芳族的发生。意义：这些研究涉及主要的公共卫生和VA医疗保健问题，即皮肤癌的发生率的日益增长。开发更有效的预防方法，例如在小鼠中表现出毒性不具有毒性的饮食GSP，需要对它们预防UVB诱导的致癌作用的机制有了改进的了解。