Vitamin D3, Calcium and Inflammation, Immunomodulation and Colonic Permeability

维生素 D3、钙与炎症、免疫调节和结肠通透性

• 批准号: 8684361
• 负责人: Veronika Fedirko
• 金额: $ 8.95万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684361
• 关键词: Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Aspirin; Bacteria; Basic Science; Bile Acids; Biological; Biological Markers; Biopsy; Blood; Blood specimen; Calcium; Calcium Carbonate; Cancer Etiology; Cancerous; Cardiovascular system; Cell Cycle; Cessation of life; Chemoprevention; Chemopreventive Agent; Cholecalciferol; Cholesterol; Chronic; Chronic Disease; Clinical Research; Clinical Trials; Colon; Colonic Polyps; Colonoscopy; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Consumption; Controlled Clinical Trials; Custom; DNA Damage; Data; Data Analyses; Development; Diet; Dietary Intervention; Dose; Double-Blind Method; Epithelial; Epithelium; Flagellin; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Heart Diseases; Human; Immunoassay; Immunoglobulin A; Immunoglobulin G; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Interferons; Interleukin-1; Interleukin-10; Interleukin-17; Interleukin-4; Interleukin-6; Interleukin-8; Interleukins; Intervention Trial; Intestines; Investigation; Joints; Laboratories; Lead; Lipopolysaccharides; Measures; Mediating; Mucous Membrane; Observational Study; Parents; Participant; Patients; Permeability; Persons; Pharmaceutical Preparations; Placebo Control; Placebos; Play; Prevention; Questionnaires; Randomized; Randomized Clinical Trials; Recurrence; Regimen; Risk; Role; Sampling; Serum; Signal Transduction; Supplementation; Surrogate Endpoint; TNF gene; Testing; Tissues; Tumor Necrosis Factor-alpha; Vitamin D; Work; adenoma; base; cancer chemoprevention; colon carcinogenesis; cost effective; cytokine; disorder risk; efficacy testing; follow-up; immune function; immunoregulation; neoplastic; novel; patient population; pressure; prevent; public health relevance; rectal; tumor

DESCRIPTION (provided by applicant): Calcium supplementation reduces sporadic colorectal adenoma recurrence, and higher serum vitamin D levels are associated with reduced risk for colorectal cancer, the second leading cause of cancer deaths in the US. Despite strong biological plausibility and supportive observational data, the independent and, especially, synergistic anti-neoplastic effects of calcium and vitamin D in humans are not clear. Proposed mechanisms have included protection of the colonic epithelium against bile acids, direct effects on the cell cycle, and modulation of growth factor signaling, inflammation, and immune function. Based on basic science and limited human evidence, we hypothesize that calcium and vitamin D supplementation decrease blood levels of biomarkers of inflammation and colonic permeability in humans. We will investigate this in an adjunct study to an ongoing multi-center, randomized, double-blind, placebo-controlled, 2 x 2 factorial chemoprevention clinical trial (n = 2,259) of supplemental calcium (1,200 mg elemental calcium daily as calcium carbonate) and vitamin D3 (1,000 IU daily), alone and in combination vs. placebo over 3 - 5 years (the 'parent study'). A sub-set of participants (n = 460) with end-of-treatment biopsies of normal-appearing rectal mucosa taken at 3- or 5-year follow-up colonoscopies is selected for this adjunct study. The aims of the proposed study are to 1) test the separate and joint effects of calcium and vitamin D supplementation on a custom panel of biomarkers of inflammation/immunomodulation (GM-CSF, IFN?, TNF¿, IL-6, IL-1¿, IL-4, IL-8, IL-10, IL-12p40, and IL-17) representing different classes of inflammatory responses in patients with previous sporadic colorectal adenomas (n = 460); 2) obtain preliminary data on the effects of supplementation with calcium and vitamin D alone or in combination on biomarkers of colonic permeability (specific IgG and IgA to lipopolysaccharide [LPS] and flagellin) (n = 120); and 3) obtain preliminary data on whether changes in the biomarker levels are associated with decreased sporadic colorectal adenoma recurrence. The proposed scope of work is limited to laboratory and statistical analyses using biological samples and questionnaire data from the 'parent study'. This adjunct study offers a unique, cost-effective opportunity in a large, ongoing trial in humans to 1) confirm anti-inflammatory effects of calcium and vitamin D in humans; 2) explore a novel hypothesis that calcium and vitamin D beneficially modulate colonic permeability; 3) elucidate the combined effects of calcium and vitamin D on biomarkers of inflammation; and 4) as a secondary objective, obtain preliminary data on whether modulation of these biomarkers predicts preventing sporadic colorectal adenoma recurrence. Elucidation of vitamin D and calcium anti-inflammatory effects is of great importance, not only to colorectal cancer chemoprevention, but also to the prevention of other inflammation-mediated chronic diseases.

描述（由申请人提供）：钙补充剂可减少散发性结直肠腺瘤复发，血清维生素D水平升高与结直肠癌风险降低相关，结直肠癌是美国癌症死亡的第二大原因。 尽管有很强的生物相容性和支持性的观察数据，但钙和维生素D在人体中的独立，特别是协同抗肿瘤作用尚不清楚。提出的机制包括保护结肠上皮免受胆汁酸的影响，对细胞周期的直接影响，以及对生长因子信号传导、炎症和免疫功能的调节。基于基础科学和有限的人类证据，我们假设钙和维生素D补充剂降低了人类炎症和结肠通透性生物标志物的血液水平。我们将在一项正在进行的多中心、随机、双盲、安慰剂对照、2 x 2因子化学预防临床试验（n = 2，259）的辅助研究中对此进行研究，该临床试验是补充钙（1，200 mg元素钙，每日碳酸钙）和维生素D3（1，000 IU，每日），单独使用和联合使用，与安慰剂相比，为期3 - 5年（"母研究"）。选择在3年或5年随访结肠镜检查时获得正常直肠粘膜治疗结束活检的受试者子集（n = 460）进行这项辅助研究。拟定研究的目的是：1）检测钙和维生素D补充剂对炎症/免疫调节生物标志物（GM-CSF、IFN？、肿瘤坏死因子、IL-6、IL-1？、IL-4、IL-8、IL-10、IL-12 p40和IL-17），其代表先前患有散发性结直肠腺瘤的患者（n = 460）中不同类型的炎症反应; 2）获得单独或联合补充钙和维生素D对结肠渗透性生物标志物影响的初步数据（脂多糖[LPS]和鞭毛蛋白的特异性IgG和IgA）（n = 120）;和3）获得关于生物标志物水平的变化是否与散发性结肠直肠腺瘤复发减少相关的初步数据。拟定的工作范围仅限于使用"母研究"的生物样本和问卷调查数据进行实验室和统计分析。 这项辅助研究在一项正在进行的大型人体试验中提供了一个独特的、具有成本效益的机会，以1）证实钙和维生素D在人体中的抗炎作用; 2）探索钙和维生素D有益地调节结肠通透性的新假设; 3）阐明钙和维生素D对炎症生物标志物的联合作用;和4）作为次要目的，获得关于这些生物标志物的调节是否预测预防散发性结肠直肠腺瘤复发的初步数据。说明维生素D和钙的抗炎作用是很大的 它不仅对结直肠癌的化学预防，而且对其他炎症介导的慢性疾病的预防具有重要意义。