Trace element supplementation to enhance calcium-mediated suppression of human colon adenoma growth

补充微量元素增强钙介导的对人结肠腺瘤生长的抑制

• 批准号: 9442883
• 负责人: JAMES VARANI
• 金额: $ 15.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9442883
• 关键词: Adenomatous Polyps; Algae; Apoptosis; Bioinformatics; Biological Markers; Biopsy; Calcium; Cations; Chemoprevention; Chemopreventive Agent; Colon; Colon Carcinoma; Colonic Adenoma; Colonic Polyps; Colorectal Cancer; Complement; DNA sequencing; Data; Development; Differentiation and Growth; Disease; Elements; Enrollment; Epidermal Growth Factor; Family history of; Freezing; Global Change; Growth; Histologic; Human; Individual; Intervention; Intervention Studies; Intervention Trial; Literature; Longevity; Magnesium; Marines; Mediating; Meta-Analysis; Minerals; Mucous Membrane; Mutation; Natural Products; Newly Diagnosed; Phenotype; Pituitary Gland; Placebos; Polyps; Positioning Attribute; Premalignant; Proteomics; Recording of previous events; Research; Risk; Seawater; Supplementation; System; Testing; Time; Tissues; Trace Elements; United States; Variant; adenoma; base; calcium intake; cancer statistics; clinical biomarkers; epidemiology study; high risk; immunohistochemical markers; intervention effect; microbiome; phenotypic biomarker; prevent; promoter; protective effect; response; skeletal; transcriptome sequencing; tumor

ABSTRACT Epidemiological and interventional studies have demonstrated an inverse relationship between calcium intake and colon polyp formation. Recent meta-analysis of the calcium chemoprevention literature indicates that the protective effects of calcium extend to colorectal cancer, itself. However, the effects are modest. It has been estimated that a reduction in tumor formation of approximately 8% might be achieved for each 300 mg per day increase in calcium intake (over a baseline of 1000 mg per day). The proposed studies will test the hypothesis that a combination of calcium and a mix of cationic trace elements will be more effective than calcium alone at suppressing the growth of human colonic adenomas (colon polyps). For the proposed studies, we will utilize human colon polyp tissue maintained in enteroid culture. We have developed a culture system to grow the premalignant human colon tissue using a minimally supplemented culture medium containing only epidermal growth factor and pituitary extract as growth promoters. Adenoma tissue in enteroid culture from 21 different cultures (representing 17 subjects) is now “banked away” as frozen stocks. DNA sequencing and bioinformatic data identifying the presence of mutations thought to influence colon polyp growth are available for each established culture. Phenotypic information (immuno-histochemical marker data) is also available for each of the premalignant tumors. In the proposed studies, enteroid cultures will be maintained under control conditions or exposed to increasing concentrations of calcium – either alone or in conjunction with additional trace elements. The effects of each intervention will be evaluated over time by assessing phenotypic markers of growth and differentiation. RNA sequencing and proteomic display differences will be used to identify global changes induced by each intervention. The use of colon enteroid cultures provides a way to determine directly if human colon polyp growth can be more effectively modulated by calcium in conjunction with additional trace elements than by calcium alone. By using cultures established from tumors of several different subjects, we are in position to determine the variability in responsiveness to each intervention as a first step toward understanding the basis for variation in response among individuals.

摘要 流行病学和干预性研究表明，钙的摄入量 和结肠息肉形成。最近对钙化学预防文献的荟萃分析表明， 钙的保护作用延伸到结肠直肠癌本身。然而，影响是有限的。已经 据估计，每天每300 mg可使肿瘤形成减少约8% 钙摄入量增加（超过每天1000 mg的基线）。拟议中的研究将检验这一假设 钙和阳离子微量元素的混合物的组合将比单独的钙更有效， 抑制人类结肠腺瘤（结肠息肉）的生长。 对于拟定的研究，我们将使用在肠样培养物中维持的人结肠息肉组织。我们有 开发了一种培养系统，使用最低限度补充的 仅含有表皮生长因子和垂体提取物作为生长促进剂的培养基。腺瘤 来自21种不同培养物（代表17名受试者）的肠样培养物中的组织现在被冷冻“储存”起来 名的股票明细金额DNA测序和生物信息学数据识别被认为影响基因突变的存在 结肠息肉生长可用于每个建立的培养物。表型信息（免疫组织化学 标记数据）也可用于每种癌前肿瘤。在拟议的研究中， 将保持在控制条件下或暴露于浓度增加的钙-单独或 与其它微量元素结合。每项干预措施的效果将随着时间的推移进行评估， 评估生长和分化的表型标记。RNA测序和蛋白质组展示 差异将用于确定每项干预措施引起的全球变化。结肠类肠炎的应用 培养物提供了一种直接确定人类结肠息肉生长是否可以更有效地调节的方法 钙与其他微量元素的结合比单独的钙。通过使用已建立的文化 从几个不同受试者的肿瘤中，我们能够确定对 每一次干预都是理解个体反应差异基础的第一步。

项目成果

Cell-Matrix Interactions Contribute to Barrier Function in Human Colon Organoids.

• DOI: 10.3389/fmed.2022.838975
• 发表时间: 2022
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Varani J;McClintock SD;Aslam MN
• 通讯作者: Aslam MN

A Multi-Mineral Intervention to Modulate Colonic Mucosal Protein Profile: Results from a 90-Day Trial in Human Subjects.

• DOI: 10.3390/nu13030939
• 发表时间: 2021-03-14
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Aslam MN;McClintock SD;Jawad-Makki MAH;Knuver K;Ahmad HM;Basrur V;Bergin IL;Zick SM;Sen A;Turgeon DK;Varani J
• 通讯作者: Varani J

A multi-mineral intervention to counter pro-inflammatory activity and to improve the barrier in human colon organoids.

• DOI: 10.3389/fcell.2023.1132905
• 发表时间: 2023
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5

Liver Protein Expression in NASH Mice on a High-Fat Diet: Response to Multi-Mineral Intervention.

纳什小鼠在高脂饮食中的肝蛋白表达：对多矿物干预的反应。

• DOI: 10.3389/fnut.2022.859292
• 发表时间: 2022
• 期刊: FRONTIERS IN NUTRITION
• 影响因子: 5
• 作者: Varani, James;McClintock, Shannon D.;Knibbs, Randall N.;Harber, Isabelle;Zeidan, Dania;Jawad-Makki, Mohamed Ali H.;Aslam, Muhammad N.
• 通讯作者: Aslam, Muhammad N.