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.

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；差距;肥胖;