Vitamin D3 Modulation of Inflammation and Lung Cancer Risk

在这个新的孢子项目中提出的研究旨在为维生素D3- 以预防肺癌为基础的方法。我们最近证明了1，25-二羟基维生素D3 维生素03的活性代谢物[1，25(OH)2D3]显著抑制肺癌细胞的生长和 拮抗核因子-kB(NF-kB)的作用。核因子-KB信号在炎症中发挥关键作用，并已 已被证明是吸烟相关的肺部炎症和癌症发生的基础。总而言之，这表明 1，25(OH)2D3可能用于肺癌的化学预防。因为系统性的1，25(OH)2D3 由于其引起高钙血症的特性，给药很复杂，我们建议使用口服 补充维生素D3以安全地达到肺组织中1，25(OH)2D3的化学保护水平。 摄入后，维生素D3很容易转化为无毒的循环前体25(OH)D3，它是 表达细胞色素P27B1的支气管上皮细胞随后在肺内转化为1，25(OH)2D3 和肺泡巨噬细胞。目的：确定维生素D3暴露对肺部炎症和 肺癌风险我们将：(目标1)利用我们孢子肺肿瘤548例患者的样本和数据 来自匹兹堡肺筛查研究(PLuSS)的180例病例和993名对照，以评估 维生素D3和核因子-KB途径基因变异、25(OH)D3血清水平与糖尿病风险的关系 肺癌；(目标2)使用来自150名PLuSS参与者的银行样本来建立 25(OH)D3血清水平和痰中炎症和肺癌风险生物标记物；(目标3)使用小鼠 量化维生素D3状态对NNK诱导的肺癌和香烟的影响的模型 烟雾诱导的肺部炎症，并检测香烟烟雾暴露对25(OH)D3的影响 维生素D3代谢酶的水平和表达；以及，(目标4)进行生物有效性研究 在肺癌高危人群中补充维生素D3。我们将评估是否 补充剂纠正维生素D3缺乏，并研究对炎症和肺癌的影响 痰中的风险生物标记物、循环炎症标记物和肺功能。

The studies proposed in this new SPORE project are designed to provide strong rationale for a vitamin D3- based approach to lung cancer prevention. We recently demonstrated that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin 03, significantly inhibits the growth of lung cancer cells and antagonizes nuclear factor-KB (NF-KB) action. NF-KB signaling plays a key role in inflammation, and has been shown to underlie smoking-associated lung inflammation and carcinogenesis. Together, this suggests that 1,25(OH)2D3 may be useful for chemoprevention of lung cancer. Because systemic 1,25(OH)2D3 administration is complicated by its hypercalcemia-inducing properties, we propose to use oral supplementation with vitamin D3 to safely achieve chemopreventive1,25(OH)2D3 levels within lung tissues. Upon ingestion, vitamin D3 is readily converted to the non-toxic circulating precursor, 25(OH)D3, which is subsequently converted to 1,25(OH)2D3 within the lung by CYP27B1-expressing bronchial epithelial cells and alveolar macrophages. To determine the impact of vitamin D3 exposure on pulmonary inflammation and lung cancer risk we will: (Aim 1) utilize samples and data from 548 cases from our SPORE Lung Tumor Registry, and 180 cases and 993 controls from the Pittsburgh Lung Screening Study (PLuSS) to evaluate the relationship between variation in vitamin D3 and NF-KB pathway genes, 25(OH)D3 serum levels, and risk of lung cancer; (Aim 2) use banked samples from 150 PLuSS participants to establish the association between 25(OH)D3 serum levels and inflammation and lung cancer risk biomarkers in sputum; (Aim 3) use murine models to quantify the effects of vitamin D3 status on NNK-induced lung carcinogenesis and cigarette smoke-induced pulmonary inflammation, and examine the impact of cigarette smoke exposure on 25(OH)D3 levels and expression of vitamin D3-metabolizing enzymes; and, (Aim 4) conduct a bioeffectiveness study of vitamin D3 supplementation in individuals at increased risk for lung cancer. We will evaluate whether supplementation corrects vitamin D3 deficiency and also investigate effects on inflammation and lung cancer risk biomarkers in sputum, circulating inflammation markers, and pulmonary function in this aim.