Project 3: Obesity/Glucose Dysregulation Project (Balmes)

代谢综合征越来越普遍，通常与肥胖和葡萄糖调节失调有关， 并会增加患心血管疾病的风险。肥胖和2型糖尿病的风险很早就开始了 儿童时期，包括在子宫内编程，以及环境因素可能在这些风险中发挥作用。这个 暴露于环境空气污染(AAP)对儿童肥胖和糖尿病风险的影响一直是 研究得很好。我们的主要假设是，暴露于AAP导致的氧化应激导致系统性 炎症，进而导致肥胖和糖尿病风险增加。次要机械论 假设是AAP诱导的Treg功能障碍会增加肥胖和糖尿病的风险。为了测试这些 假设，分析儿童在不同发展阶段的表现是零碎的、自然的 将进行历史设计(0-2岁、7-9岁、16-19岁和19-22岁)。详细的历史信息， 将收集所有受试者的人体测量数据和血液样本。暴露于AAP的风险将被估计 从子宫里开始。拟议的研究有以下目的：a)确定慢性接触是否 对于急性胰腺炎，尤其是多环芳烃(PAHs)，与HbAlc、BMI和 8-异前列腺素(氧化应激的生物标记物)，CRP(全身炎症的生物标记物)，瘦素，脂联素， 和高密度脂蛋白(脂肪和葡萄糖代谢异常的生物标志物)；b)确定 AAP诱导的T调节(Treg)和T效应细胞功能障碍与HbAlc和HbAlc增加有关 BMI；以及c)确定Foxp3的表观遗传修饰是否存在Treg 功能障碍和糖化血红蛋白或体重指数。使用经验丰富的现场中心工作人员，两个中心各有220名儿童 将从弗雷斯诺招募较年轻的年龄组和每个较年长组的100名受试者并进行跟踪 根据年龄的不同而变化的期限。与暴露核心合作产生终生污染物 接触史和生物统计学--建立边缘结构模型的流行病学核心，多学科 研究小组将对长期接触空气之间的联系进行分析 污染物(或Treg功能参数)和HbAlc、BMI或感兴趣的生物标记物。

Metabolic syndrome is increasingly prevalent, is usually associated with obesity and glucose dysregulation, and leads to increased risk of cardiovascular disease. Risks of obesity and diabetes type 2 begin in eariy childhood, including in utero programming, and environmental factors likely play a role in these risks. The effect of exposure to ambient air pollution (AAP) on risk of obesity and diabetes among children has been well studied. Our primary hypothesis is that oxidative stress induced by exposure to AAP leads to systemic inflammation which in turn leads to increased risk of obesity and diabetes. A secondary mechanistic hypothesis is that AAP-induced Treg dysfunction increases risks of obesity and diabetes. To test these hypotheses, analyses of children in the different stages of development represented in a piecewise, natural history design will be conducted (ages 0-2, 7-9, 16-19, and 19-22). Detailed historical information, anthropometric data, and blood samples will be collected for all subjects. Exposures to AAP will be estimated from in utero onward. The proposed study has the following aims: a) to determine whether chronic exposure to AAP, especially polycyclic aromatic hydrocarbons (PAHs), is associated with increased HbAlc, BMI, and 8-isoprostane (biomarker of oxidative stress), CRP (biomarker of systemic inflammation), leptin, adiponectin, and high-density lipoprotein (biomarkers of abnormal fat and glucose metabolism); b) to determine whether AAP-induced dysfunction of T regulatory (Treg) and T effector cells is associated with increased HbAlc and BMI; and c) to determine whether epigenetic modification of Foxp3 underiies the associations between Treg dysfunction and HbAlc or BMI. Using an experienced field center staff, 220 children in each ofthe two younger age groups and 100 subjects in each of the older groups will be recruited from Fresno and followed for variable durations depending on age. Working with the Exposure Core to generate lifetime pollutant exposure histories and the Biostatistics-Epidemiology Core to build marginal structural models, the multidisciplinary research team will conduct analyses of the associations between chronic exposures to air pollutants (or Treg functional parameters) and HbAlc, BMI, or the biomarkers of interest.