A Pilot Metabolomic Study of the Effects of Vitamin D and Calcium Supplementation

维生素 D 和钙补充剂影响的初步代谢组学研究

• 批准号: 8637394
• 负责人: John Anthony Baron
• 金额: $ 16.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-17 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637394
• 关键词: Affect; Androgen Receptor; Antineoplastic Agents; Bile Acids; Bioinformatics; Biological Markers; Biometry; Biopsy; Calcium; Catabolism; Cataloging; Catalogs; Cell Cycle; Characteristics; Chemoprevention; Chemopreventive Agent; Cholecalciferol; Chronic Disease; Clinical; Clinical Data; Clinical Investigator; Clinical Trials; Collaborations; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Controlled Clinical Trials; Correlation Studies; Data; Databases; Development; Diet; Dissociation; Double-Blind Method; Estrogen Receptors; Fourier Transform; Future; Genes; Genetic Variation; Genome; Goals; Growth Factor; Human; Human Genome; Individual; Inflammation; Intervention Trial; Investigation; Ions; Laboratories; Lead; Life Style; Lipids; Liquid Chromatography; Maps; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Pathway; Methodology; Methods; Mucous Membrane; Myocardial Ischemia; North Carolina; Parents; Participant; Pathway interactions; Patients; Phenotype; Pilot Projects; Placebo Control; Placebos; Plasma; Prevention; Randomized; Recurrence; Reducing Agents; Research Personnel; Resolution; Risk; Risk-Benefit Assessment; Sample Size; Sampling; Signal Transduction; Spectrum Analysis; Supplementation; Testing; Tissues; Universities; Variant; Visit; Vitamin D; adenoma; carcinogenesis; disorder risk; efficacy testing; follow-up; immune function; innovation; metabolomics; novel; pre-clinical; prevent; rectal; tool

This collaborative proposal between the University of North Carolina ¿ Chapel Hill and Emory University is an adjunct pilot metabolomic study to an ongoing multi-center, randomized, double-blind, placebo-controlled, modified 2 x 2 factorial chemoprevention clinical trial (R01 CA98286; PI: J. Baron) (n = 2,259) that is testing the efficacy of supplemental vitamin D3 (1,000 IU daily) and calcium (1,200 mg elemental calcium daily), alone and in combination vs. placebo over 3 ¿ 5 years in preventing sporadic colorectal adenoma recurrence (the ¿parent study¿). The objective of this proposal is to establish a new interactive collaboration between clinical researchers in the parent study and metabolomics experts, and to incorporate a novel high-resolution metabolomics approach into the parent study to better understand the independent and synergistic antineoplastic actions and other effects of vitamin D and calcium in humans. Our innovative approach utilizes high-resolution mass spectrometry to measure >20,000 metabolites, and provides a unique workflow using false discovery rates (FDR) to prioritize metabolites for subsequent study, correlation analysis to enhance identification of relevant metabolic modules associated with these prioritized metabolites, pathway mapping using available online tools to identify relevant metabolic pathways, and post-hoc application of ion dissociation (MS/MS) spectroscopy to representative metabolites to confirm pathway identification. In the pilot study we will obtain preliminary data on the effects of supplementation with vitamin D and/or calcium on individual metabolites and metabolic pathways in a sub-set of participants (n = 120) with baseline and follow-up biopsies of normal-appearing rectal mucosa. The preliminary results obtained from this pilot study will lead to larger, full-scale, metabolomic investigations to elucidate 1) the individual and combined effects of vitamin D and calcium on metabolomic pathways in humans (thus providing a more comprehensive assessment of the benefits and risks of these heavily promoted agents as supplements), 2) whether these metabolomic changes correlate with genetic variation and systemic and tissue-specific biomarkers in humans (and thus their direct relevance to the chemoprevention of colorectal neoplasms), and 3) whether the metabolomic changes predict the occurrence of sporadic colorectal adenomas in humans, thus paving the way for the development of treatable biomarkers of risk for colorectal neoplasia that are analogous to lipid profiles for the prevention of ischemic heart disease. Elucidating the effects of vitamin D and/or calcium supplementation on individual metabolites and metabolomic pathways may inform the potential use of these chemopreventive agents for preventing colorectal neoplasms, and, possibly, other chronic diseases.

这项北卡罗来纳州查佩尔山大学和埃默里大学之间的合作提案是一项正在进行的多中心、随机、双盲、安慰剂对照、改良2 × 2因子化学预防临床试验的辅助试验代谢组学研究（R01 CA98286; PI：J. Baron）（n = 2，259）正在测试补充维生素D3的功效（每日1,000 IU）和钙（每日1,200 mg元素钙），单独和联合与安慰剂相比，在预防散发性结直肠腺瘤复发方面超过3）。该提案的目的是在母研究中的临床研究人员和代谢组学专家之间建立一种新的互动合作，并将一种新的高分辨率代谢组学方法纳入母研究中，以更好地了解维生素D和钙在人体中的独立和协同作用以及其他作用。我们的创新方法利用高分辨率质谱法测量> 20，000种代谢物，并提供独特的工作流程，使用错误发现率（FDR）为后续研究确定代谢物的优先级，进行相关性分析以增强与这些优先代谢物相关的相关代谢模块的识别，使用可用的在线工具进行途径映射以识别相关代谢途径，和事后应用离子解离（MS/MS）光谱法对代表性代谢物进行确认途径鉴定。在初步研究中，我们将获得补充维生素D和/或钙对个体代谢物和代谢途径的影响的初步数据，这些数据来自一组参与者（n = 120），这些参与者具有正常直肠粘膜的基线和随访活检。从这项试点研究中获得的初步结果将导致更大的，全面的，代谢组学研究，以阐明1）维生素D和钙对人体代谢途径的单独和联合作用（从而对这些大力推广的药物作为补充剂的益处和风险进行更全面的评估），2）这些代谢组学变化是否与人类的遗传变异以及全身和组织特异性生物标志物相关（以及因此它们与结肠直肠肿瘤的化学预防的直接相关性），和3）代谢组学变化是否预测人类中散发性结肠直肠腺瘤的发生，从而为开发可治疗的结肠直肠瘤形成风险生物标志物铺平了道路，所述生物标志物类似于用于预防缺血性心脏病的脂质分布。阐明维生素D和/或钙补充剂对个体代谢物和代谢组学途径的影响可能会告知这些化学预防剂用于预防结直肠肿瘤以及可能的其他慢性疾病的潜在用途。