Prevention of photocarcinogenesis by dietary immunomodulation

描述（由申请人提供）： 摘要在美国，人类皮肤过度暴露于太阳紫外线（UV）辐射是黑色素瘤和非黑色素瘤皮肤癌发生的主要病因，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，膳食葡萄籽原花青素（GSP）在体内小鼠模型中提供针对UV诱导的皮肤致癌作用的显著保护，并且进一步证明膳食GSP提供针对UV诱导的免疫抑制的显著保护，UV诱导的免疫抑制是皮肤癌的公认风险因素。所提出的研究的目标是通过以下方式建立膳食GSP用于纠正与光致癌相关的UV诱导的免疫抑制的机制：（i）鉴定膳食GSP改善UV辐射诱导的免疫抑制和DNA损伤的机制;和（ii）确定这些机制对GSP介导的皮肤癌预防的贡献。 目前，已知以产生环丁烷嘧啶二聚体（CPD）的形式的UV诱导的DNA损伤是癌症的危险因素，并且是UV介导的免疫抑制的重要分子触发剂，并且UV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细胞的功能受损相关。因此，关键问题是GSP是否在多个方面起作用以防止或纠正UV诱导的免疫抑制或通过阻断引发免疫抑制的早期事件起作用。我们的初步研究表明，GSP具有增强UV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可以增强UV暴露树突状细胞中CPD的去除，并恢复树突状细胞介导的活性，包括刺激T细胞。值得注意的是，在DNA修复缺陷的小鼠中，饮食GSP不抑制UV诱导的免疫抑制。总之，这些数据表明的假设，即在树突状细胞中的GSP的UVB诱导的DNA损伤的修复是至关重要的UV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）确定饮食GSPs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）确定膳食GSP是否通过增强T细胞活化来抑制UV诱导的免疫抑制，（3）确定饮食中的GSP是否抑制UV诱导的调节性T细胞的发育;和（4）确定饮食中的GSP对光致癌作用的抑制是否通过DNA修复介导。意义：这些研究解决了一个主要的公共卫生和VA医疗保健问题，即，皮肤癌发病率的上升。开发更有效的预防方法，如在小鼠中没有毒性的膳食GSP，需要更好地了解它们预防UVB诱导的致癌作用的机制。

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.