Project 3: Obesity/Glucose Dysregulation Project (Balmes)

代谢综合征越来越普遍，通常与肥胖和血糖失调有关， 并导致心血管疾病风险增加。肥胖和2型糖尿病的风险开始在早期 童年，包括在子宫内的编程和环境因素可能在这些风险中发挥作用。的 暴露于环境空气污染（AAP）对儿童肥胖和糖尿病风险的影响， 好好研究。我们的主要假设是暴露于AAP诱导的氧化应激导致全身性 炎症，这反过来又导致肥胖和糖尿病的风险增加。第二机械 一种假说是AAP诱导的Treg功能障碍增加肥胖和糖尿病的风险。测试这些 假设，分析儿童在不同阶段的发展，在一个分段的，自然的 将进行历史设计（0-2岁、7-9岁、16-19岁和19-22岁）。详细的历史资料， 将收集所有受试者的人体测量数据和血液样本。将估计AAP暴露量 从子宫里开始拟议的研究有以下目的：a）确定长期接触是否 AAP，尤其是多环芳烃（PAH），与HbAlc、BMI和 8-异前列烷（氧化应激生物标志物），CRP（全身炎症生物标志物），瘦素，脂联素， 和高密度脂蛋白（异常脂肪和葡萄糖代谢的生物标志物）; B）确定是否 AAP诱导的调节性T细胞（Treg）和效应性T细胞的功能障碍与HbA 1c和HbA 1c的增加有关。 c）确定Foxp 3的表观遗传修饰是否是Treg与BMI之间的关联的基础。 功能障碍和HbAlc或BMI。利用一个有经验的现场中心工作人员， 将从弗雷斯诺招募年轻组和每个老年组的100名受试者，并进行随访 时间长短取决于年龄。与暴露核心合作产生终身污染物 暴露历史和生物流行病学核心，以建立边缘结构模型，多学科 研究小组将分析长期暴露于空气中 污染物（或Treg功能参数）和HbAlc、BMI或感兴趣的生物标志物。

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.