XENOBIOTIC METABOLISM AND CANCER IN GLUTEN-SENSITIVE MACAQUES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 采用非人灵长类动物（NHP）面筋敏感模型，研究了面筋敏感恒河猴（Macaca mulatta）小肠组织中与膳食面筋变化相关的基因扰动。缓解和复发的阶段是通过无麸质（GFD）和含麸质（GD）饮食的管理在麸质敏感动物中完成的。在GFD或GD时通过儿科内窥镜从十二指肠获得的夹取活组织检查用于制备总RNA和基因谱分析，使用商业恒河猴微阵列（Agilent Technologies）靶向超过20，000个基因的表达。与正常健康对照相比，谷蛋白敏感猕猴表现出差异基因表达诱导GD。虽然观察到的基因扰动被分为12个重叠的类别之一，本研究的重点是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。在谷蛋白敏感的动物中，GD时显示出解毒功能丧失，这是代谢致癌物的必要性。与肌动蛋白-胶原-MMP基因网络表达改变相关的促癌因子增加，同时抑癌因子减少。此外，麸质敏感的猕猴在停止食用麸质后，差异表达的基因数量减少，包括癌症相关基因。总之，这些发现表明，在癌症研究中，谷蛋白敏感的恒河猴可能会扩大效用。

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.