Early Life Determinants of Obesity in U.S. Urban Low Income Minority Birth Cohort

 描述（由申请人提供）：幼儿肥胖不仅会导致短期的社会、心理和健康影响，而且会增加日后肥胖的可能性，并伴有许多可能的慢性疾病，如心血管疾病、糖尿病和癌症。动物和人类研究都明确表明，在发育的关键早期阶段的扰动可能对代谢疾病的标志物（如肥胖和胰岛素抵抗）产生终身的，有时是不可逆的不良影响。肥胖的多因素病因学沿着发育过程使得早期生活因素和儿童肥胖之间的联系成为一个复杂的系统，需要多学科系统的方法。虽然其潜在机制尚不完全清楚，但表观遗传机制可能起重要作用。我们的工作表明，DNA甲基化模式在出生时可检测到，在生命的头两年是动态的，个体差异相当大;母亲孕前BMI与出生时与慢性疾病相关的后代DNA甲基化改变有关。然而，没有研究追踪从早期生活因素到出生和幼儿期表观遗传变化到城市低收入非裔美国人和西班牙裔儿童中儿童肥胖和相关表型的发展的途径，这些儿童受到肥胖流行病的影响。本申请的第一个目的是确定肥胖发展的早期生命风险和保护因素。我们将通过利用现有的广泛数据库和对3,000名波士顿出生队列（BBC）儿童从出生到10岁的持续随访，调查肥胖发展中的产前和出生到24个月的综合因素。我们将特别注意那些需要进一步研究的潜在重要因素。第二个目的是探索早期生活因素和儿童肥胖之间的表观基因组的介导作用，使用现有的全基因组DNA甲基化数据在出生和2岁时测量（发现样本）;并在独立样本中复制焦磷酸测序的重要发现。第三个目标是开发一个虚拟出生队列（VBC）系统动力学模型，以代表和帮助更好地理解连接早期生活因素与随后的儿童肥胖症的复杂系统，并确定最能影响儿童肥胖症随后发展的关键可修改因素;并测试在各种情况下将这些因素修改到不同程度的干预效果。这种高度创新和高效的方法整合了来自 BBC，然后纳入一个计算模拟模型，以更好地了解儿童肥胖和表观遗传机制的早期生活决定因素。VBC还将使我们能够探索BBC的发现如何适用于其他地点和情况，从而帮助推广我们的发现。该项目的影响在于有可能为新的和 在最关键的发育窗口期和美国人口中最脆弱的群体中，采取可持续的战略来减轻儿童肥胖的负担。

 DESCRIPTION (provided by applicant): Obesity in a young child can not only result in short-term social, psychological, and health effects but also increases the probability to obesity later n life with many possible accompanying chronic conditions such as cardiovascular disease, diabetes, and cancer. Both animal and human studies unequivocally show that perturbations during critical early periods of development can have a life-long, sometimes irreversible, adverse impact on markers of metabolic disease like adiposity and insulin resistance. Obesity's multi-factorial etiology along with developmental processes makes the links between early life factors and childhood obesity a complex system requiring a multi-disciplinary systems approach. Although the potential mechanism is not completely clear, epigenetic mechanisms may play an important role. Our work has shown considerable individual variability of DNA methylation patterns detectable at birth and dynamic in the first two years of life; and that maternal prepregnancy BMI is associated with offspring DNA methylation alterations at birth relevant to chronic disease. However, no study has traced pathways from early life factors through epigenetic changes at birth and early childhood to the development of childhood obesity and related phenotypes among urban low- income African American and Hispanic children who have been disproportionally affected by the obesity epidemic. The first aim of this application is to identify early life risk and protective factors for obesity development. We will investigate a comprehensive array of prenatal and birth to 24-month factors in the development of obesity by leveraging the extensive existing databases and ongoing follow-up of 3,000 Boston Birth Cohort (BBC) children from birth to age 10 years. We will pay particular attention to those potentially important factors that require further study. The second aim is to explore the mediating effect of the epigenome between early life factors and childhood obesity, using existing genome-wide DNA methylation data measured at birth and age 2 years (discovery sample); and replicate important findings by pyrosequencing in an independent sample. The third aim is to develop a Virtual Birth Cohort (VBC) systems dynamics model to represent and help better understand the complex system connecting early life factors with subsequent childhood obesity and determine the key modifiable factors that will most impact the subsequent development of childhood obesity; and test the intervention effects if modifying these factors to different degrees under a variety of scenarios. This highly innovative and efficient approach integrates "real data" from the BBC and then incorporates into a computational simulation model to better understand early life determinants of childhood obesity and epigenetic mechanisms. The VBC also will allow us to explore how findings from the BBC may apply to other locations and circumstances, thus helping generalize our findings. The impact of this project lies in the potential to inform new and sustainable strategies to reduce the burden of childhood obesity during the most critical developmental windows and among the most vulnerable segments of the US population.