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

基本信息

批准号：
8828139
负责人：
Veronika Fedirko
金额：
$ 8.17万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828139
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 Health 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 rectal tumor

项目摘要

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（由应用提供）：补充钙可减少零星的结直肠腺瘤复发，而血清维生素D水平较高与结直肠癌的风险降低有关，这是美国癌症死亡的第二大主要原因。尽管强烈的生物学合理性和支持性的观察数据，但钙和维生素D在人类中的独立，尤其是钙和维生素D的协同抗抑制作用尚不清楚。提出的机制包括保护结肠上皮对胆汁酸的保护，对细胞周期的直接影响以及生长因子信号传导，感染和免疫功能的调节。基于基础科学和有限的人类证据，我们假设补充钙和维生素D会降低人类感染和结肠通透性的血液水平。我们将在一项辅助研究中对正在进行的多中心，随机，双盲，安慰剂对照，2 x 2 forsorial化学预防临床试验（n = 2,259）补充钙（每天为1,200 mg元素钙作为钙含量为1,200 mg元素钙）和'每日的维生素d3（1,000 IU），''''''''''为这项辅助研究选择了在3或5年随访的结肠镜下进行的正常直肠粘膜的参与者（n = 460）的子集（n = 460）。拟议的研究的目的是1）测试钙和维生素D补充钙和维生素D的单独和关节作用，对炎症/免疫调节的生物标志物的定制小组（GM-CSF，IFN？，TNF？，IL-6，IL-6，IL-1？，IL-1？，IL-4，IL-4，IL-8，IL-8，IL-8，IL-10，IL-10，IL-10，IL-12P40，IL-17），IL-17，IL-17，IL-17，IL-17，零星结直肠腺瘤（n = 460）; 2）获得有关单独补充钙和维生素D的影响的初步数据，或者合并对结肠通透性的生物标志物（特异性IgG和IgA对脂多糖[LPS]和鞭毛蛋白）（n = 120）； 3）获得有关生物标志物水平变化是否与改善零星结直肠腺瘤复发有关的初步数据。提出的工作范围仅限于实验室和统计分析，并使用“父母研究”中的生物学样本和问卷数据进行了统计分析。这项辅助研究在人类正在进行的大型，正在进行的试验中提供了独特的，具有成本效益的机会1）证实钙和维生素D对人类的抗炎作用； 2）探讨一个新的假设，即钙和维生素D良好地调节结肠通透性； 3）阐明钙和维生素D对炎症生物标志物的综合作用； 4）作为次要目标，获得有关这些生物标志物的调节是否预测可预防偶然结直肠腺瘤复发的初步数据。阐明维生素D和钙抗炎作用的很大重要性，不仅对结直肠癌化学预防，而且对预防其他感染介导的慢性疾病。