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

项目总结： 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的紊乱 与肥胖和几种主要癌症的发生有关。 然而，很少有研究试图确定这些与癌症相关的生物分子的变异来源， 这可能是由于能量因素之间的复杂相互关系，如饮食、体力活动和 睡眠模式。精力因素也可能受到宏观层面的因素的影响，如邻里社会 经济状况(SES)和建成环境。最后，这些关系可能会受到基因的调节 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大约750名女性(包括25%的非裔美国女性)能量因素和癌症相关生物标记物之间的关系。能量因素将包括：(1)用双标记水(DLW)衡量的能量消耗；(2)用胰岛素指数和胰岛素负荷衡量的膳食胰岛素需求量；(3)通过 重复加速度计测量；(4)通过两个1周睡眠记录评估睡眠持续时间。与癌症相关的生物标志物将包括(1)胰岛素-胰岛素样生长因子轴成分 (2)脂肪因子(总的和游离的瘦素[瘦素与可溶性瘦素受体的比率-SOB-R]和脂联素)；(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与建成环境(由县蔓延指数评估)和癌症相关生物标记物的关系，并勾勒出这些宏观变量、能量因素、生物标记物和肥胖之间的联系路径。在第三个目标中，我们 将在护士健康研究和健康专业人员跟踪研究中，利用现有的全基因组关联研究(GWAS)数据，在8,000名男性和女性中检查与胰岛素抵抗或胰岛素分泌相关的遗传因素是否改变了行为因素(饮食胰岛素需求、体力活动和睡眠时间)和宏观因素(社区环境和建筑环境)与肥胖风险和长期体重增加之间的关系。这项研究的发现不仅将为 能源平衡与癌症风险之间关系的社会、行为和生物途径，不仅有助于制定多层次的降低风险战略，从饮食和生活方式的改变到城市规划和社区推广肥胖和癌症预防。因为这项拟议的研究是基于完善的持续队列，以及对能量因素的详细测量 (DLW、饮食、体力活动和睡眠)和血液采集由NCI通过为期两年的刺激拨款(2009-2011年)提供资金，这是非常划算和及时的。

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.