Environmental and Lifestyle Factors, Obesity, and Cancer-related Biomarkers

项目摘要： 胰岛素-胰岛素样生长因子（IGF）轴、性激素水平和脂肪细胞因子紊乱 与肥胖和几种主要癌症的发展有关。 然而，很少有研究试图确定这些癌症相关生物标志物变异的起源， 这可能是由于能量因素之间复杂的相互关系，如饮食，体育活动， 睡眠模式能量因素也可能受到宏观层面因素的影响，如邻里社会关系 经济地位（SES）和建筑环境。最后，这些关系可能受到遗传因素的调节。 变种，但对此知之甚少。在第一个目标中，我们将在护士健康研究中检查约750名妇女（包括25%的非洲裔美国妇女）的能量因素和癌症相关生物标志物之间的关联。积极因素包括：（1）通过双标记水（DLW）测量的能量消耗;（2）通过胰岛素指数和胰岛素负荷测量的膳食胰岛素需求;（3）通过 重复的加速计测量;和（4）通过两个1周睡眠日志评估的睡眠持续时间。癌症相关生物标志物将包括（1）胰岛素-IGF轴组分 （空腹胰岛素、胰岛素原、C肽、IGF-1和IGFBP-3）;（2）脂肪因子（总瘦素和游离瘦素[瘦素与可溶性瘦素受体- sOB-R的比值]和脂联素）;和（3）性激素结合球蛋白（SHBG）和雌二醇。在第二个目标中，我们将研究社区SES和建筑环境（由县蔓延指数评估）和癌症相关生物标志物之间的关系，并描绘连接这些宏观变量，能量因素，生物标志物和肥胖的途径。第三个目标，我们 将研究与胰岛素抵抗或胰岛素分泌相关的遗传因素是否会改变行为之间的关联，（饮食胰岛素需求，体力活动和睡眠时间）和宏观水平（社区社会经济地位和建筑环境）因素和肥胖和长期体重增加的风险之间的8，000名男性和女性在护士健康研究和卫生专业人员随访研究与可用的全基因组关联研究（GWAS）数据。这项研究的结果不仅将提供有关 社会、行为和生物途径是能量平衡和癌症风险之间关系的基础，也有助于制定多层次的降低风险战略，包括饮食和生活方式的改变，以及城市规划和社区宣传肥胖和癌症预防。因为拟议的研究是基于完善的正在进行的队列，以及能量因素的详细测量， (DLW饮食、体力活动和睡眠）和血液收集的资金来自NCI的2年刺激赠款（2009-2011年），这是非常具有成本效益和及时的。

Project Summary: Disturbances in the insulin- insulin-like grovirth factor (IGF) axis, levels of sex hormones, and adipocytokines have been implicated in pathways connecting obesity with the development of several major cancers. However, few studies have sought to determine the origins of variation in these cancer-related biomakers, which may be due to complex interrelationships between energetic factors such as diet, physical activity, and sleep patterns. Energetic factors may also be impacted by macro-level factors such as neighborhood social economical status (SES) and built environment. Finally, these relationships may be moderated by genetic variants, but little is known regarding this. In the first Aim, we will examine associations between energetic factors and cancer-related biomarkers in about 750 women (includinq 25% African American women) in the Nurses' Health Study. Energetic factors will include: (1) energy expenditure measured by doubly labeled water (DLW); (2) dietary insulin demand measured by insulin index and insulin load; (3) physical activity assessed by repeated accelerometer measurements; and (4) sleep duration assessed by two 1-week sleep logs. Cancerrelated biomarkers will include (1) insulin-IGF axis components (fasting insulin, proinsulin, C-peptide, IGF-1, and IGFBP-3); (2) adipokines (total and free leptin [the ratio of leptin to soluble leptin receptor - sOB-R] and adiponectin); and (3) sex hormone-binding globulin (SHBG) and estradiol. In the second Aim, we will examine the relationships between neighborhood SES and built environment (assessed by the county sprawl index) and cancer-related biomarkers, and delineate the pathways linking these macro-level variables, energetic factors, biomarkers, and obesity. In the third Aim, we will examine whether genetic factors related to insulin resistance or insulin secretion modify the associations between behavioral (dietary insulin demand, physical activity, and sleep duration) and macro-level (neighborhood SES and built environment) factors and risk of obesity and long-term weight gain among 8,000 men and women in the Nurses' Health Study and Health Professionals Follow-up Study with available genome-wide association studies (GWAS) data. The findings from this study will not only provide insights into social, behavioral, and biological pathways underlying the relationship between energy balance and cancer risk, but also facilitate development of multi-tiered risk reduction strategies spanning diet and lifestyle modification to urban planning and community outreach for obesity and cancer prevention. Because the proposed study is based on well-established ongoing cohorts, and detailed measures of energetic factors (DLW, diet, physical activity, and sleep) and blood collection have been funded through a 2-year stimulus grant (2009-2011) by NCI, it is extremely cost-effective and timely.