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Prevention of photocarcinogenesis by dietary immunomodulation

Prevention of photocarcinogenesis by dietary immunomodulation
通过饮食免疫调节预防光致癌
批准号:
8803280
负责人:
SANTOSH KUMAR KATIYAR
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-04-01 至 2016-03-31

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中文摘要
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英文摘要
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.
期刊论文(8)
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会议论文
Dietary grape seed proanthocyanidins inactivate regulatory T cells by promoting NER-dependent DNA repair in dendritic cells in UVB-exposed skin.
膳食葡萄籽原花青素通过促进暴露于 UVB 的皮肤树突状细胞中 NER 依赖性 DNA 修复来灭活调节性 T 细胞。
DOI: 10.18632/oncotarget.17867
发表时间: 2017
期刊: Oncotarget
影响因子: --
作者: [Vaid,Mudit, Prasad,Ram, Singh,Tripti, Katiyar,SantoshK]
通讯作者: Katiyar,SantoshK
DOI: 10.1038/s41598-017-01659-7
发表时间: 2017-05-04
期刊: Scientific reports
影响因子: 4.6
作者: [Pal HC, Prasad R, Katiyar SK]
通讯作者: Katiyar SK
DOI: 10.3390/molecules21121758
发表时间: 2016-12-21
期刊: Molecules (Basel, Switzerland)
影响因子: --
作者: [Pal HC, Katiyar SK]
通讯作者: Katiyar SK
DOI: 10.1371/journal.pone.0060749
发表时间: 2013
期刊: PloS one
影响因子: 3.7
作者: [Singh T, Katiyar SK]
通讯作者: Katiyar SK
共 7 条
    Prevention of UV-carcinogenesis through DNA methylation-dependent immunomodulation
    Prevention of UV-carcinogenesis through DNA methylation-dependent immunomodulation
    Proanthocyanidins,Novel bioactive components for prevention of melanoma invasion
    Proanthocyanidins,Novel bioactive components for prevention of melanoma invasion
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