XENOBIOTIC METABOLISM AND CANCER IN GLUTEN-SENSITIVE MACAQUES

麸质敏感猕猴的异生代谢与癌症

• 批准号: 8358154
• 负责人: KAROL SESTAK
• 金额: $ 3.72万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358154
• 关键词: Actins; Animals; Biopsy; Carcinogens; Categories; Childhood; Collagen; Cytochrome P450; Diet; Disease remission; Drug Metabolic Detoxication; Duodenum; Endoscopes; Family; Funding; Genes; Gluten; Grant; Intestines; Macaca; Macaca mulatta; Malignant Neoplasms; Matrix Metalloproteinases; Metalloproteinase Gene; Modeling; National Center for Research Resources; Preparation; Primates; Principal Investigator; RNA; Relapse; Research; Research Infrastructure; Resources; Source; Staging; Technology; Tissue-Specific Gene Expression; Tissues; United States National Institutes of Health; Withdrawal; Xenobiotic Metabolism; anticancer research; cost; nonhuman primate; prevent

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta). Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets. Pinch biopsies, obtained by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies), targeting expression of over 20,000 genes. When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories, this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes. A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 采用面筋敏感的非人灵长类动物(NHP)模型，研究了面筋敏感猕猴(Macaca Mulatta)小肠组织中与膳食面筋变化相关的基因扰动。在对面筋敏感的动物中，通过给予无面筋(GFD)和含面筋(GD)饮食来完成缓解和复发阶段。使用商用恒河猴基因芯片(Agilent Technologies)，利用儿科内窥镜在GFD或GD期间从十二指肠获取的夹点活检组织，用于制备总RNA和基因图谱，靶向表达超过20,000个基因。与正常健康对照组相比，面筋敏感猕猴在GD诱导下的基因表达存在差异。虽然观察到的基因扰动被归类为12个重叠类别之一，但本研究重点关注与癌症相关的基因网络，如细胞色素P450家族(解毒功能)和肌动蛋白-胶原-基质金属蛋白酶(MMP)基因。在面筋敏感的动物中，在GD期间，解毒功能的丧失与代谢致癌物的必要性平行。随着肌动蛋白-胶原-基质金属蛋白酶基因网络表达的改变，促癌因子的增加和防癌因子的同时减少。此外，当停止食用面筋时，对面筋敏感的猕猴显示出差异表达基因的数量减少，包括与癌症相关的基因。综上所述，这些发现表明，对面筋敏感的恒河猴在癌症研究中的应用可能会扩大。