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: 10684760
• 负责人: JAMES R HEBERT
• 金额: $ 110.47万
• 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/10684760
• 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; Disparity; 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; Macrophage; Malignant Neoplasms; Mediator; 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; experimental study; fecal transplantation; gut microbes; gut microbiota; high risk; human study; in vivo; inflammatory marker; intestinal barrier; lifestyle intervention; 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项目利用了我们在大肠癌流行病学方面的专业知识（CRC）；差异；肥胖; 代谢失调，炎症的重要表现；微生物组；动物CRC模型；和 生活方式干预试验解决了早期发病CRC（EOCRC）（即<50年）的日益增长的问题。 肥胖和饮食驱动代谢失调。因此，了解饮食与肥胖之间的相互作用 是理解Eocrc的起源的关键，以及其他与肥胖有关的癌症的群体）。这个项目 将解决涉及生活方式干预措施的重要临床试验和机理研究 eocrc。我们打算解决这一差距；并拥有代表完件的跨学科团队 这样做的背景。我们专注于肠道微生物的饮食调节，以减少荟萃症和 随后的肥胖症代谢功能障碍，目的是防止Eocrc。我们将执行1） CRC风险较高的成年人和儿童二元组的炎症性饮食干预试验。我们也会 进行完整的机械动物研究，基于和利用我们在机械方面的专业知识 肥胖和CRC的研究。这项工作得到了我们过去几十年来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，CCCR， 2002年 - 现在 - 专门研究CRC的小鼠模型）； （2）预防癌症和控制 计划（CPCP，2000年 - 现在 - 专门研究癌症和生活方式干预的流行病学 癌症试验，重点是癌症差异。构成拟议赠款地址的两个项目 人类研究和实验室动物实验代表的两个具体目标：即1： 建立抗炎饮食在肥胖的高风险非洲 - 非洲饮食的代谢保护作用 美国（AA）和欧美（EA）成年人和儿童减少炎症，如 胰岛素抵抗（HOMA-IR），IGF-1，肿瘤坏死因子alpha的稳态模型评估 （TNFα），白介素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 代谢功能障碍和相关CRC风险的逆转。这通过 进行类似输入（饮食），中间端点（炎症，炎症， 微生物组）和结果（与CRC相关）。我们假设抗炎的饮食干预将 通过对肠道菌群的调节作用来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有关的作用 在癌变中很重要，因此可能对Eocrc产生深远影响，对 其他与肥胖有关的癌症，并通过解决机制来推动领域有很大的希望 这驱动了与健康相关的巨大差距，这些差距始终不利于非洲裔美国人。