A Transdisciplinary Approach to Investigating Metabolic Dysregulation in Obese Parent and Child Dyads and Risk of Colorectal Cancer

这个U01项目利用了我们在结直肠癌(CRC)流行病学方面的专业知识；差异；肥胖； 代谢失调，炎症的重要表现；微生物组；动物CRC模型；以及 生活方式干预试验，以解决日益严重的早发性结直肠癌(EOCRC)问题(即，50年)。 肥胖和饮食导致代谢失调。因此，了解饮食和肥胖之间的相互作用 是理解EOCRC和其他一系列与肥胖相关的癌症的起源的关键)。这个项目 将解决缺乏关键的临床试验和涉及生活方式干预的机制研究 EOCRC。我们打算弥补这一差距；并让代表跨学科的团队相互补充 这样做的背景。我们专注于肠道微生物的饮食调节，以减少代谢和 肥胖患者随后的代谢功能障碍，目的是预防EOCRC。我们将表演一场反- 成人和儿童结直肠癌高危人群的炎症性饮食干预试验。我们也会 进行补充的机械动物研究，以我们在机械方面的专业知识为基础并加以利用 关于肥胖和结直肠癌的研究。这项工作得到了我们在过去几十年中建立的基础设施的支持 在南卡罗来纳大学(UofSC)的两个关键中心：(1)结肠癌研究中心(CCCR， 2002年至今-专门研究结直肠癌的小鼠模型)；以及(2)癌症预防和控制 方案(CPCP，2000年至今--专门研究癌症流行病学和生活方式干预 癌症试验，重点是癌症差异。组成拟议赠款的两个项目的地址 人体研究和实验动物实验所代表的两个具体目标： 在肥胖、高风险的非洲人中建立抗炎饮食的代谢保护作用 美国(AA)和欧洲-美国(EA)成人和儿童在减少炎症方面的作用 胰岛素抵抗(HOMA-IR)、胰岛素样生长因子-1、肿瘤坏死因子-α的稳态模型评估 (肿瘤坏死因子α)、白介素6(IL-6)和C反应蛋白，以及创造更有利的微生物群 签名；2：建立肠道微生物作为抗炎饮食摄入和抗炎饮食之间的中介 代谢功能障碍逆转和相关的结直肠癌风险。这是对人类研究的补充，通过 使用相似的输入(饮食)、中间终点(炎症、 微生物组)和结果(与儿童权利公约有关)。我们假设抗炎饮食干预将 通过对肠道微生物区系的调节作用，减少代谢功能障碍和代谢燃烧。 这项工作的结果将解决代谢失调与已知因素有关的作用 在癌症的发生中很重要，因此可能对EOCRC产生深远的影响，对 其他与肥胖相关的癌症，并有很大希望通过解决机制来推动该领域的发展 这导致了与健康相关的巨大差距，这些差距一直不利于非裔美国人。

This U01 project leverages our expertise in the epidemiology of colorectal cancer (CRC); disparities; obesity; metabolic dysregulation, an important manifestation of inflammation; the microbiome; animal CRC models; and lifestyle intervention trials to address the growing problem of Early-Onset CRC (EOCRC) (i.e., <50 years). Adiposity and diet drive metabolic dysregulation. So, understanding the interaction between diet and adiposity are key to understanding the genesis of EOCRC – and an array of other obesity-related cancers). This project will address the absence of critical clinical trials and mechanistic studies involving lifestyle interventions for EOCRC. We intend to address this gap; and have the transdisciplinary team representing complementary backgrounds to do so. We focus on dietary modulation of gut microbes to reduce metaflammation and subsequent metabolic dysfunction in obesity, with a goal of preventing EOCRC. We will perform 1) an anti- inflammatory dietary intervention trial in dyads of adults and children at elevated risk for CRC. We also will conduct a complementary mechanistic animal study that builds on and leverages our expertise in mechanistic studies on obesity and CRC. This work is supported by infrastructure that we have built over the past decades in two key centers at the University of South Carolina (UofSC): (1) Center for Colon Cancer Research (CCCR, 2002 - present – which specializes in mouse models of CRC); and (2) the Cancer Prevention and Control Program (CPCP, 2000 - present – which specializes in the epidemiology of cancer and lifestyle intervention trials for cancer, with a focus on cancer disparities. The two projects that comprise the proposed grant address two Specific Aims that are represented by the human study and laboratory animal experiment: i.e. ,1: To establish the metabolic protective effects of an anti-inflammatory diet in obese, high-risk African- American (AA) and European-American (EA) adults and children in reducing inflammation as indicated by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), IGF-1, Tumor Necrosis Factor alpha (TNFα), Interleukin 6 (IL-6), and C-Reactive Protein (CRP), and a creating more favorable microbiome signature; 2: To establish gut microbes as mediators between anti-inflammatory dietary input and reversal of metabolic dysfunction and associated CRC risk. This complements the human study by carrying out pre-clinical murine model studies with similar inputs (diet), intermediate endpoints (inflammation, microbiome), and outcomes (CRC-related). We hypothesize that an anti-inflammatory dietary intervention will reduce metabolic dysfunction and metainflammation through regulatory effects on gut microbiota. Results from this work will address the role of metabolic dysregulation in relation to factors that are known to be important in carcinogenesis, that therefore could have profound effects on EOCRC, have implications for other obesity-related cancers, and have great promise for moving the field forward by addressing mechanisms that drive large health-related disparities that consistently disfavor African Americans.