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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（由申请人提供）：补充钙可减少散发性结直肠腺瘤复发，较高的血清维生素D水平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。尽管具有很强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侵害，直接影响细胞周期，调节生长因子信号，炎症和免疫功能。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可以降低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 × 2因子化学预防临床试验（n = 2259）的辅助研究中对此进行调查，该临床试验使用补充钙（每日1200毫克单质钙作为碳酸钙）和维生素D3（每日1000 IU）单独或联合使用，与安慰剂相比，持续3 - 5年（“母研究”）。在3年或5年的随访结肠镜检查中，对治疗结束后表现正常的直肠粘膜进行活组织检查的参与者（n = 460）被选为本辅助研究的一部分。拟议研究的目的是：1)测试钙和维生素D补充剂对炎症/免疫调节生物标志物(GM-CSF， IFN？， TNF¿，IL-6, IL-1¿，IL-4, IL-8, IL-10， IL-12p40和IL-17)代表既往散发性结直肠腺瘤患者不同类型的炎症反应（n = 460）；2)获得单独或联合补充钙和维生素D对结肠通透性生物标志物（对脂多糖[LPS]和鞭毛蛋白的特异性IgG和IgA）影响的初步数据（n = 120）；3)获得生物标志物水平的变化是否与散发性结直肠腺瘤复发减少相关的初步数据。建议的工作范围仅限于使用来自“母体研究”的生物样本和问卷数据进行实验室和统计分析。这项辅助研究为一项正在进行的大型人体试验提供了一个独特的、具有成本效益的机会：1)确认钙和维生素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；4)作为次要目标，获得这些生物标志物的调节是否预测预防散发性结直肠腺瘤复发的初步数据。阐明维生素D和钙的抗炎作用很大