Chemoprotective effects of natural products on colonic adult stem cells

天然产物对结肠成体干细胞的化学保护作用

• 批准号: 8196591
• 负责人: Robert Stephen Chapkin
• 金额: $ 29.75万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-08 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196591
• 关键词: Address; Adult; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Biological Factors; Botanicals; Cancer Biology; Carcinogens; Cell Cycle; Cells; Chemopreventive Agent; Chemoprotective Agent; Chromatin; Chromatin Structure; Chronic; Citrus; Code; Colitis; Colon; Colon Adenocarcinoma; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Curcumin; DNA; DNA Damage; Data; Development; Diagnostic Neoplasm Staging; Diet; Disease Progression; Environmental Risk Factor; Epigenetic Process; Epithelial Cells; Exons; Exposure to; Functional RNA; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Goals; Health; Histones; Inflammation; Internal Ribosome Entry Site; Intestinal Cancer; Intestines; Laboratories; LacZ Genes; Link; Location; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; Messenger RNA; MicroRNAs; Modification; Mus; Oncogenes; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Population; Post-Transcriptional Regulation; Reducing Agents; Research; Resolution; Route; Safety; Saline; Signal Pathway; Signal Transduction; Stem cells; Tamoxifen; Transcript; Translational Repression; Tumeric; Tumor stage; adult stem cell; cancer chemoprevention; cancer risk; carcinogenesis; chromatin immunoprecipitation; colon carcinogenesis; colonic crypt; daughter cell; genome-wide; histone modification; insight; mouse model; novel; promoter; research study; response; self-renewal; stem; stem cell biology; stem cell niche; stem cell population; stemness; tumor

DESCRIPTION (provided by applicant): We have demonstrated that chemoprotective diets containing turmeric (curcumin) and citrus (limonin) bioactives reduce chronic inflammation and colon cancer risk. With respect to cancer biology, recent observations demonstrate that crypt stem cells are the cells-of-origin of intestinal cancer. Since non-coding microRNA-mediated translational repression and changes to chromatin structure may be linked to the development of colon cancer, it is vital that the effect of chemopreventive diets on microRNAs, their messenger RNA (mRNA) targets, and epigenetic modifications on both the histone and DNA levels in intestinal stem cells be determined. However, to date, the effect of dietary botanicals on genome-wide chromatin epigenetic modifications, microRNAs, and mRNA populations in intestinal stem cells, crypts and tumors has not been determined. Therefore, we hypothesize that a chemoprotective diet, containing curcumin and/or the citrus bioactive limonin, will modulate the stem cell transcriptome, resulting in a favorable shift in disease progression. Aim 1 will use highly novel stem cell specific Lgr5-LacZ and Lgr-EGFP mice to quantify the number and spatio-temporal location of stem cells, DNA damage and targeted apoptosis in the colonic crypt at the initiation and tumor stages of colon carcinogenesis following exposure to diets containing curcumin, limonin, and their mixture. Aim 2 will use the Lgr5-EGFP mouse to investigate the effect of disease progression on microRNAs and their post-transcriptionally regulated mRNA targets in colonic stem cells, intact colonic crypts and tumors following carcinogen/inflammation or saline (control) exposure. Aim 3 will generate high-resolution genome- wide "chromatin-state" maps for (i) intestinal epithelial cell crypts, and (ii) colonic tumors using chromatin immunoprecipitation in order to assess the effect of diet and colitis-associated colon carcinogenesis on epigenetic modifications at both the histone and DNA levels. It is anticipated that novel stem cell signaling networks and markers will emerge from these studies. The proposed studies will promote our understanding of how botanicals impact critical signaling pathways during normal intestinal development and malignant transformation, including self-renewal of stem cells. PUBLIC HEALTH RELEVANCE: The proposed studies will promote our understanding of how dietary chemoprotective natural botanical products, e.g., curcumin, citrus-derived limonin, and their mixture, impact critical signaling pathways during normal intestinal development and malignant transformation, including self-renewal of stem and progenitor cells.

描述（由申请人提供）：我们已经证明，含有姜黄（姜黄素）和柑橘（柠檬苦素）生物活性物质的化学保护饮食可以降低慢性炎症和结肠癌的风险。在癌症生物学方面，最近的观察表明隐窝干细胞是肠癌的起源细胞。由于非编码 microRNA 介导的翻译抑制和染色质结构的变化可能与结肠癌的发展有关，因此化学预防饮食对 microRNA、其信使 RNA (mRNA) 靶点的影响以及对结肠癌和结肠癌的表观遗传修饰的影响至关重要。确定肠道干细胞中的组蛋白和 DNA 水平。然而，迄今为止，饮食植物对肠道干细胞、隐窝和肿瘤中全基因组染色质表观遗传修饰、microRNA 和 mRNA 群体的影响尚未确定。因此，我们假设含有姜黄素和/或柑橘类生物活性柠檬苦素的化学保护性饮食将调节干细胞转录组，从而导致疾病进展的有利转变。目标 1 将使用高度新颖的干细胞特异性 Lgr5-LacZ 和 Lgr-EGFP 小鼠来量化暴露后结肠癌发生起始阶段和肿瘤阶段的结肠隐窝中干细胞的数量和时空位置、DNA 损伤和靶向细胞凋亡含有姜黄素、柠檬苦素及其混合物的饮食。目标 2 将使用 Lgr5-EGFP 小鼠研究致癌物/炎症或盐水（对照）暴露后疾病进展对结肠干细胞、完整结肠隐窝和肿瘤中 microRNA 及其转录后调节 mRNA 靶标的影响。目标 3 将使用染色质免疫沉淀生成 (i) 肠上皮细胞隐窝和 (ii) 结肠肿瘤的高分辨率全基因组“染色质状态”图，以评估饮食和结肠炎相关结肠癌发生对表观遗传的影响组蛋白和 DNA 水平上的修饰。预计这些研究将出现新的干细胞信号网络和标记。 拟议的研究将促进我们对植物如何影响正常肠道发育和恶性转化（包括干细胞自我更新）过程中关键信号通路的理解。 公共健康相关性：拟议的研究将促进我们对膳食化学保护性天然植物产品（例如姜黄素、柑橘来源的柠檬苦素及其混合物）如何影响正常肠道发育和恶性转化（包括干细胞自我更新）过程中的关键信号传导途径的理解和祖细胞。