Prevention of photocarcinogenesis by dietary immunomodulation

描述(由申请人提供)： 摘要人体皮肤过度暴露于太阳紫外线(UV)辐射是美国黑色素瘤和非黑色素瘤皮肤癌发生的主要原因，其中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，饮食中的葡萄籽原花青素(GSP)在体内小鼠模型中对紫外线诱导的皮肤癌具有显著的保护作用，并进一步证明，饮食中的葡萄籽原花青素对紫外线诱导的免疫抑制提供了显著的保护，而紫外线诱导的免疫抑制是皮肤癌的一个公认的危险因素。这项研究的目的是建立饮食GSP纠正紫外线诱导的与光癌相关的免疫抑制的机制：(I)确定饮食GSP改善紫外线诱导的免疫抑制和DNA损伤的机制；以及(Ii)确定这些机制在GSP介导的皮肤癌预防中的作用。目前已知，紫外线诱导的DNA损伤以环丁烷嘧啶二聚体(CPDS)的产生为形式，是癌症的危险因素，是紫外线介导的免疫抑制的重要分子触发因素，紫外线介导的免疫抑制与抑制细胞的诱导以及树突状细胞和效应T细胞的功能受损有关。因此，关键的问题是，GSP是在多个方面起作用来预防或纠正紫外线诱导的免疫抑制，还是通过阻断启动免疫抑制的早期事件来起作用。我们的初步研究表明，GSP具有促进紫外线暴露皮肤中CPD+细胞的清除或修复的能力，我们的初步数据进一步表明，GSP可以促进紫外线暴露的树突状细胞中CPD的清除，并恢复树突状细胞介导的活动，包括刺激T细胞。值得注意的是，饮食中的GSP不能抑制那些DNA修复缺陷小鼠的紫外线诱导的免疫抑制。综上所述，这些数据表明，GSP对UVB诱导的树突状细胞DNA损伤的修复是其对UV诱导的免疫抑制和光癌的化学预防作用的关键。我们提出了四个相互关联的特定目标，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)确定饮食GSP是否通过恢复树突状细胞的活性来抑制紫外线诱导的耐受性树突状细胞的发展；(2)确定饮食GSP是否通过促进T细胞激活来抑制紫外线诱导的免疫抑制；(3)确定饮食GSP是否抑制紫外线诱导的调节性T细胞的发展；以及(4)确定饮食GSP对光致癌的抑制是否通过DNA修复来介导。意义：这些研究涉及公共卫生和退伍军人管理局医疗保健的一个主要问题，即皮肤癌发病率的不断上升。开发更有效的预防方法，例如饮食中对小鼠没有毒性的GSP，需要更好地理解它们防止UVB诱导的癌症发生的机制。

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.