Role of Vitamin D in cutaneous DNA repair

维生素 D 在皮肤 DNA 修复中的作用

• 批准号: 10045940
• 负责人: DENNIS H OH
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045940
• 关键词: Address; Affect; Anabolism; Animal Model; Animals; Biological; Biological Assay; Biological Models; CYP27B1 gene; Calcium; Cellular biology; Chemicals; Cholecalciferol; Clinical Trials; Complement; Coupled; Cutaneous; Cytochrome P450; DNA Damage; DNA Repair; DNA Repair Gene; DNA lesion; Data; Dermatologist; Disease; Dose; Enzyme Inhibition; Exposure to; Future; Gene Expression; General Population; Genes; Genomics; Health; Health Benefit; Health Policy; Human; In Vitro; Individual; Institute of Medicine (U.S.); Ketoconazole; Knockout Mice; Laboratories; Lesion; Life; Ligands; Measures; Mediating; Metabolism; Minerals; Mus; Mutation Analysis; Mutation Spectra; Nucleotide Excision Repair; Pathway interactions; Pharmacology; Phenotype; Photosynthesis; Physiological; Play; Production; Proteins; Public Health; Radiation Induced DNA Damage; Recommendation; Reporting; Research; Research Proposals; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Sun Exposure; Sunburn; Sunlight; Supplementation; TP53 gene; Testing; The Sun; UV carcinogenesis; UV induced; Ultraviolet Rays; Uncertainty; Veterans; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; Vitamin D3 Receptor; Work; active duty; base; bone health; carcinogenesis; dietary guidelines; experimental study; gene repair; inhibitor/antagonist; insight; keratinocyte; military service; mouse model; non-genomic; nutrition; photolysis; photoprotection; prevent; protective behavior; repaired; response; service member; skin cancer prevention; small hairpin RNA; sun protection; tumor; ultraviolet; ultraviolet irradiation

Both vitamin D deficiency and skin cancers arising from epidermal keratinocytes are highly prevalent in Veterans. Although exposure to the ultraviolet (UV) wavelengths normally found in sunlight initiates vitamin D biosynthesis, the practice is not currently recommended since UV is also the principal cause of skin cancers. However, there remains uncertainty as to whether the relatively low doses sufficient for vitamin D production in the skin are associated with a meaningful risk of skin cancer in healthy individuals, and the Institute of Medicine's report on this topic identified resolving this issue as a major research need. Based on work in both our laboratory and those of others, there is evidence that UV-inducible mechanisms such as DNA repair might be directly coupled to vitamin D signaling. For example, we have observed that mice lacking the vitamin D receptor are prone to develop UV-induced epidermal tumors, and vitamin D and some of its metabolites induce DNA repair proteins. On the other hand, mice unable to synthesize the most biologically active form of vitamin D are not tumor-prone. However, it remains possible that one or more of the multiple other vitamin D metabolites does have anti-photocarcinogenic effects, including induction of nucleotide excision repair activity, the principal mechanism for removing UV-induced DNA lesions. The overall hypothesis of this research proposal is that vitamin D or its derivatives stimulate compensatory mechanisms to repair the collateral DNA damage associated with its own UV-mediated photosynthesis and thus minimizes photocarcinogenic effects. In Aim I, cultured keratinocytes and epidermal explants derived from CYP27B1-null mice will be used to compare the activities of major vitamin D3 metabolites for their effects on nucleotide excision repair. Both exogenous supplementation and chemical inhibition to modulate endogenous vitamin D metabolite levels will be employed, and expression of repair genes as well as repair activity and UV resistance will be assayed. In Aim II, both genomic and non-genomic mechanisms for vitamin D's effects on DNA repair will be investigated. Cultured keratinocytes and mouse epidermal explants will be used to assess the relevance of the vitamin D receptor in DNA repair, and the assembly and stability of nucleotide excision repair factors at lesions. Aim III will use mice treated with the most active vitamin D derivative and the broad cytochrome P450 inhibitor, ketoconazole, to assess whether supplementation or depletion of the major vitamin D3 metabolites protects animals from photocarcinogenesis, or predisposes them to it. Mutational spectra of tumors in the TP53 and XPC genes will also be analyzed to understand the pathways involved. These studies should make an important contribution to understanding the physiological and cellular mechanistic role of vitamin D in regulating DNA repair in skin and in suppressing UV photocarcinogenesis. The resulting fundamental biological insights may allow a rational basis to help guide health policy decisions regarding vitamin D in nutrition and skin cancer prevention for Veterans as well as the general population.

维生素 D 缺乏症和表皮角质形成细胞引起的皮肤癌在以下人群中都非常普遍： 退伍军人。尽管暴露于阳光中常见的紫外线 (UV) 波长会引发维生素 D 生物合成，目前不推荐这种做法，因为紫外线也是皮肤癌的主要原因。 然而，相对较低的剂量是否足以产生维生素 D，仍存在不确定性。 皮肤与健康个体患皮肤癌的显着风险相关，并且研究所 关于这个主题的医学报告将解决这个问题确定为主要的研究需求。基于两者的工作 我们的实验室和其他实验室，有证据表明，DNA 修复等紫外线诱导机制可能 直接与维生素 D 信号传导耦合。例如，我们观察到缺乏维生素 D 的小鼠 受体容易发生紫外线诱发的表皮肿瘤，而维生素 D 及其一些代谢物可诱发 DNA 修复蛋白。另一方面，小鼠无法合成最具生物活性的维生素形式 D 不具有肿瘤倾向。然而，多种其他维生素 D 中的一种或多种仍然有可能 代谢物确实具有抗光致癌作用，包括诱导核苷酸切除修复活性， 消除紫外线引起的 DNA 损伤的主要机制。本研究的总体假设 建议是维生素 D 或其衍生物刺激补偿机制来修复侧支 DNA 与其自身紫外线介导的光合作用相关的损伤，从而最大限度地减少光致癌作用。 在目标 I 中，来自 CYP27B1 缺失小鼠的培养角质形成细胞和表皮外植体将用于 比较主要维生素 D3 代谢物的活性及其对核苷酸切除修复的影响。两个都 外源性补充和化学抑制调节内源性维生素 D 代谢物水平将 并检测修复基因的表达以及修复活性和抗紫外线能力。在 目标 II，将研究维生素 D 对 DNA 修复影响的基因组和非基因组机制。 培养的角质形成细胞和小鼠表皮外植体将用于评估维生素 D 的相关性 DNA修复中的受体，以及病变处核苷酸切除修复因子的组装和稳定性。目标三 将使用用最活跃的维生素 D 衍生物和广泛的细胞色素 P450 抑制剂治疗的小鼠， 酮康唑，评估补充或消耗主要维生素 D3 代谢物是否能起到保护作用 动物免受光致癌作用，或使其易患光致癌作用。 TP53 和 TP53 肿瘤的突变谱 还将分析 XPC 基因以了解所涉及的途径。这些研究应该使 对于理解维生素 D 的生理和细胞机制作用具有重要贡献 调节皮肤 DNA 修复并抑制紫外线光致癌。由此产生的基本生物学 见解可能提供合理的基础来帮助指导有关营养和维生素 D 的卫生政策决策。 退伍军人和普通人群的皮肤癌预防。