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

采用跨学科方法研究肥胖父母和儿童二人组的代谢失调和结直肠癌风险

• 批准号: 10505332
• 负责人: JAMES R HEBERT
• 金额: $ 111.66万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505332
• 关键词: 3 year old; Address; Adipocytes; Adipose tissue; Adult; African American; African American population; Age-Years; American; Animal Experiments; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Bacteria; Biological Assay; C-reactive protein; Cancer Control; Cancer Intervention; Cancer Model; Cells; Child; Chronic; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Communication; Complement; Complement 2; Consumption; Diet; Dietary Intervention; Enrollment; Epidemiology; European; Goals; Grant; Health; High Fat Diet; Human; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Influentials; Infrastructure; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Interleukin-6; Intervention; Intervention Trial; Laboratory Animals; Link; Literature; Malignant Neoplasms; Mediator of activation protein; Medical; Metabolic; Metabolic dysfunction; Modeling; Obese Mice; Obesity; Obesity associated cancer; Outcome; Paper; Parents; Pathogenesis; Population; Publishing; Race; Risk; Role; Science; Somatomedins; South Carolina; Study models; System; TNF gene; Testing; Unhealthy Diet; Universities; Work; adenoma; adiponectin; anticancer research; associated symptom; cancer epidemiology; cancer health disparity; cancer prevention; carcinogenesis; colorectal cancer progression; colorectal cancer risk; cytokine; dietary; early onset colorectal cancer; epidemiology study; experience; fecal transplantation; gut microbes; gut microbiota; high risk; human study; in vivo; inflammatory marker; intestinal barrier; lifestyle intervention; macrophage; microbiome; microbiome signature; microbiota; mouse model; obesity in children; pre-clinical; prevent; programs; protective effect; protective factors; racial difference; racial identity; response; systemic inflammatory response; tumorigenesis

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.

该 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； 代谢失调，炎症的重要表现；和 生活方式干预试验旨在解决日益严重的早发性结直肠癌 (EOCRC)（即 <50 岁）问题。 肥胖和饮食会导致代谢失调，因此，了解饮食和肥胖之间的相互作用。 是了解 EOCRC 以及一系列其他与肥胖相关的癌症起源的关键）。 将解决缺乏涉及生活方式干预的关键临床试验和机制研究的问题 我们打算解决这一差距；并拥有代表互补的跨学科团队。 我们专注于肠道微生物的饮食调节，以减少代谢炎症和 肥胖引起的代谢功能障碍，以预防 EOCRC 为目标，我们将进行 1) 抗- 我们还将针对结直肠癌风险较高的成人和儿童进行炎症饮食干预试验。 进行一项补充性机械动物研究，该研究建立在并利用我们在机械方面的专业知识 这项工作得到了我们过去几十年建立的基础设施的支持。 南卡罗来纳大学 (UofSC) 的两个重要中心：(1) 结肠癌研究中心 (CCCR， 2002 年至今 – 专门研究 CRC 小鼠模型）；以及 (2) 癌症预防和控制 项目（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，这两个项目构成了拟议的拨款地址。 以人体研究和实验室动物实验为代表的两个具体目标：即 1： 确定抗炎饮食对肥胖、高危非洲人的代谢保护作用 美国 (AA) 和欧美 (EA) 成人和儿童在减少炎症方面的作用，如 胰岛素抵抗 (HOMA-IR)、IGF-1、肿瘤坏死因子 α 的稳态模型评估 (TNFα)、白细胞介素 6 (IL-6) 和 C 反应蛋白 (CRP)，以及创造更有利的微生物组 签名；2：建立肠道微生物作为抗炎饮食输入和 逆转代谢功能障碍和相关的 CRC 风险，这补充了人体研究。 使用相似的输入（饮食）、中间终点（炎症、 微生物组）和结果（CRC 相关）。我们追求抗炎饮食干预。 通过对肠道微生物群的调节作用减少代谢功能障碍和元炎症。 这项工作的结果将解决代谢失调与已知因素相关的作用。 在致癌过程中很重要，因此可能对 EOCRC 产生深远影响，对 其他与肥胖相关的癌症，并有望通过解决机制来推动该领域向前发展 这导致了与健康相关的巨大差异，而这些差异始终不利于非裔美国人。