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: 9240533
• 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 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240533
• 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; Diet; Disease; Dose; Enzyme Inhibition; Exposure to; Future; Gene Expression; General Population; Genes; Genomics; Guidelines; Health; Health Benefit; Health Policy; Human; In Vitro; Individual; Institute of Medicine (U.S.); Ketoconazole; Knockout Mice; Laboratories; Lesion; Life; Ligands; Measures; Mediating; Metabolism; Military Personnel; 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; base; bone health; carcinogenesis; experimental study; gene repair; inhibitor/antagonist; insight; keratinocyte; 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.

由表皮角质形成细胞引起的维生素D缺乏症和皮肤癌在 退伍军人。尽管暴露于通常在Sunlight中发现的紫外线（UV）波长启动维生素D 生物合成，目前不建议这种做法，因为紫外线也是皮肤癌的主要原因。 但是，关于相对较低剂量是否足以在维生素D产生的情况下仍然存在不确定性 皮肤与健康个体中皮肤癌的有意义风险有关，研究所 Medicine关于该主题的报告确定将此问题解决为一项重大研究需求。基于两者的工作 我们的实验室和其他实验室，有证据表明，紫外线诱导的机制（例如DNA修复）可能 直接与维生素D信号耦合。例如，我们观察到缺乏维生素D的小鼠 受体容易发展为紫外线诱导的表皮肿瘤，维生素D及其某些代谢产物诱导 DNA修复蛋白。另一方面，小鼠无法合成最活跃的维生素形式 D不容易肿瘤。但是，一个或多种其他维生素D中的一个或多种可能仍然有可能 代谢产物确实具有抗磷酸癌作用，包括诱导核苷酸切除修复活性， 去除紫外线诱导的DNA病变的主要机制。这项研究的总体假设 建议是维生素D或其衍生物刺激补偿机制来修复附带DNA 损害与其自身的紫外线介导的光合作用相关，从而最大程度地减少了光芳基效应。 在AIM I中，培养的角质形成细胞和表皮外植体衍生自CYP27B1-NULL小鼠将用于 比较主要维生素D3代谢产物对核苷酸切除修复的影响。两个都 外源补充和调节内源性维生素D代谢物水平的化学抑制作用将 将使用修复基因以及修复活性和抗紫外线耐药性的表达。在 AIM II，将研究维生素D对DNA修复作用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衍生物和宽细胞色素P450抑制剂治疗的小鼠， 酮康唑，评估主要维生素D3代谢物的补充或耗竭保护 动物是从光钙局发生的，或使其易于使用。 TP53和 还将分析XPC基因以了解所涉及的途径。这些研究应该成为 对了解维生素D在理解生理和细胞机械作用的重要贡献 调节皮肤中的DNA修复和抑制紫外线光碳纤维生成。由此产生的基本生物学 见解可以允许合理依据，以帮助指导营养中有关维生素D的健康政策决策 退伍军人和普通人群的皮肤癌预防。