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.

抽象的 流行病学和介入研究表明钙摄入量之间存在反比关系 和结肠息肉的形成。钙化学预防文献的最近荟萃分析表明 钙的保护作用扩展到结直肠癌本身。但是，效果是适中的。它一直 据估计，每天300毫克的肿瘤形成减少约8％ 钙摄入量的增加（超过每天1000毫克的基线）。拟议的研究将检验假设 在 抑制人类结肠腺瘤（结肠息肉）的生长。 对于拟议的研究，我们将利用维持在肠动物培养的人类结肠息肉组织。我们有 开发了一种培养系统，使用最小补充的人类结肠前结肠组织 培养基仅包含表皮生长因子和居民提取物作为生长启动子。腺瘤 从21种不同培养物（代表17个受试者）的肠培养中的组织现在被“储存”为冻结 股票。 DNA测序和生物信息学数据识别出来的突变的存在 每种既定的培养物都可以使用结肠息肉的生长。表型信息（免疫 - 历史化学） 标记数据）也可用于每个预立肿瘤。在拟议的研究中，肠培养 将保持在控制条件下或暴露于钙浓度增加 - 单独或 结合其他痕量元素。每种干预措施的影响将随着时间的流逝评估 评估生长和分化的表型标记。 RNA测序和蛋白质组学显示 差异将用于确定每种干预诱导的全球变化。结肠肠内的使用 培养提供了一种直接确定人类结肠息肉生长是否可以更有效调节的方法 通过钙与其他痕量元素结合使用，而不是单独使用钙。通过使用建立的文化 从几个不同受试者的肿瘤中，我们可以确定对反应性的可变性 每种干预措施是理解个体响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.

• 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.