Mechanisms of Energy Balance and Cancer Prevention

描述(由申请人提供)： 我们建议在西雅图TREC中心使用几种不同的研究设计，结合医学、细胞生物学、动物模型、流行病学、营养学、胃肠病学、分子生物学、肥胖学、内分泌学、肥胖症、心脏病学、免疫学、生物统计学、数学、运动生理学和行为科学的科学家的跨学科贡献，阐明能量平衡的组成部分与癌症过程之间的联系。西雅图TREC中心的首要主题将是确定能量平衡在包括细胞培养、动物模型、小规模人体实验研究和种群水平实验工作在内的广泛环境中改变和影响整个生命周期的癌症发生过程的机制。在项目1中，我们将结合我们实验室正在进行的基础研究工作，以创新的方法分析高血糖、高胰岛素血症和炎症对与肿瘤发生相关的生长、增殖和生存途径的细胞影响。在项目2中，我们将在动物模型中确定热量限制和运动单独和联合对乳腺致癌反应的影响，以及能量平衡变化调节癌症发展的机制。在项目3中，我们将在交叉临床试验设计中调查瘦身和肥胖青少年和年轻人对实验性高血糖负荷饮食和低血糖负荷饮食的代谢和癌症生物标志物的反应。在项目4中的一项随机对照试验中，我们将单独和共同调查饮食减肥和锻炼对炎症、DNA损伤和修复的生物标记物的影响，以及基因多态对这些关联的影响。在项目5中，我们将在低收入和少数民族人群占多数的地理区域测试工作场所肥胖预防干预措施的体重指数、胰岛素抵抗和炎症标志物。我们的新实验室工作将包括测试对血清蛋白质组学的干预效果，并在一个开发项目中测试对代谢组学的干预效果，以确定饮食、运动和肥胖的生物信号。我们的研究人员在能量平衡和癌症方程的组成部分方面拥有丰富的专业知识，并将为整个TREC计划提供重要的科学领导、培训和贡献。

DESCRIPTION (provided by applicant): We propose in the Seattle TREC Center to elucidate the pathways linking components of energy balance to the cancer process using several different study designs, with the transdisciplinary contributions of scientists from medicine, cell biology, animal models, epidemiology, nutrition, gastroenterology, molecular biology, obesity, endocrinology, obesity, cardiology, immunology, biostatistics, mathematics, exercise physiology, and behavioral science. The overarching theme of the Seattle TREC Center will be determining the mechanisms by which energy balance modifies and influences the process of carcinogenesis across the lifespan in a broad range of settings including cell culture, animal models, small-scale human experimental studies, and population-level experimental work. In Project 1 we will bring together basic research efforts underway in our laboratories in an innovative approach to analyzing the cellular effects of hyperglycemia, hyperinsulinemia, and inflammation on growth, proliferation and survival pathways relevant to oncogenesis. In Project 2 we will determine, in an animal model, the effects of caloric restriction and exercise, alone and in combination, on the carcinogenic response in the mammary gland and on the mechanisms by which changes in energy balance modulate the development of cancer. In Project 3 we will investigate the metabolic and cancer biomarker response to experimental high and low glycemic load diets in lean and obese teenagers and young adults in a crossover clinical trial design. Within a randomized controlled trial in Project 4, we will investigate the effects of dietary weight loss and exercise, alone and together, on biomarkers of inflammation, and DNA damage and repair, and the influences of genetic polymorphisms on these associations. In Project 5 we will test a worksite obesity prevention intervention in a geographic area with large representation of low income and minority individuals on body mass index and markers of insulin resistance and inflammation. Our novel laboratory work will include testing intervention effects on serum proteomics and, in a developmental project, on metabolomics, in order to identify biological signals of dietary, exercise, and adiposity. Our investigators have a wealth of expertise in the components of the energy balance and cancer equation, and will provide important scientific leadership, training, and contributions to the overall TREC program.