Epigenomics of Air Pollution driven Inflammation, Obesity and Insulin Resistance

 描述（由申请人提供）：肥胖和II型糖尿病（T2 D）在全球范围内呈流行性增加。流行病学研究表明，空气污染是 胰岛素抵抗（IR）和T2 D发展的环境风险因素。然而，空气污染暴露导致进行性IR导致T2 D的机制仍不清楚。越来越多的证据表明，IR，这往往先于T2 D的几十年，可能是通过表观遗传变化调制。妊娠期和幼儿期是对空气污染更加脆弱的时期，也是表观遗传模式首次建立的阶段。我们之前已经在小鼠模型中建立了集中的环境污染（CAP）暴露>12周会增强肥胖、IR和T2 D的发展，并且还诱导IR和T2 D的典型异常，包括全身组织中免疫功能的变化（下丘脑、循环和脂肪），棕色脂肪组织功能降低，肝内质网应激/脂肪变性和胰岛素应答组织如肝、骨骼肌和脂肪中胰岛素信号传导的原型缺陷。我们已经进一步证明，早期是一个脆弱的时期，因为在此期间暴露于CAP会加速IR的发展，血糖控制的明显变化在<10周内发展。此外，这些缺陷继发于活性氧（ROS）途径的关键改变和胰岛素反应组织中的炎症。CAP暴露还导致全基因组的5-mC增加。假设：空气污染暴露导致全球表观遗传改变，导致靶组织中的代谢重新编程，导致肥胖和胰岛素抵抗。我们认为，在脆弱的发展时期，（例如在子宫内或幼儿期）特别容易发生表观基因组的不可逆变化和IR的持续性。该项目将利用最先进的环境暴露设施，暴露科学的调查专业知识，疾病途径和表观遗传学可在马里兰州和约翰霍普金斯大学的大学来实现这些具体的目标。SA1：表征响应于空气污染的表观基因组变化，其可能先于胰岛素抵抗表型的发展或与胰岛素抵抗表型的发展重叠。SA 2：定义与生命早期CAP暴露相关的IR和整体表观基因组变化。SA 3：确定停止空气污染暴露是否逆转胰岛素抵抗和相应的表观基因组变化。SA 4：整合跟踪IR表型发展的表观基因组和转录组扰动。这些动物模型研究与我们的良好优化的控制空气污染暴露，导致代谢综合征将揭示全面的表观基因组标记，表型之前，并在目标和替代组织之间的保守。这些数据将为验证机制以及对人类研究的解释提供新的线索。

 DESCRIPTION (provided by applicant): Obesity and type II diabetes (T2D) have been increasing globally at epidemic proportions. Epidemiological studies indicate that air pollution is an environmental risk factor for development of insulin resistance (IR) and T2D. However, the mechanisms by which air pollution exposure causes progressive IR leading to T2D remain unclear. There is increasing evidence that IR, which often precedes the T2D by decades, may be modulated through epigenetic changes. Gestation and early childhood are periods of enhanced vulnerability to air pollution and also coincide with the stage at which epigenetic patterning is first established. We have previously established in mouse models that concentrated ambient pollution (CAP) exposure for >12 weeks potentiates the development of obesity, IR and T2D, and also induces a range of abnormalities that are prototypical for IR and T2D, including changes in immune function in systemic tissues (hypothalamus, circulation and adipose), reduced brown adipose tissue function, hepatic endoplasmic reticulum stress/steatosis and prototypical defects in insulin signaling in insulin response tissues such as liver, skeletal muscle and adipose. We have further demonstrated that early age is a period of vulnerability, as exposure to CAP during this period accelerates development of IR with overt changes in glycemic control developing in <10 weeks. Further, these defects are secondary to critical alterations in reactive oxygen species (ROS) pathways and inflammation in insulin responsive tissues. CAP exposure also results in genome-wide increases in in 5-mC. Hypothesis: Air pollution exposure results in global epigenetic alterations that result in metaboli re-programming in target tissues leading to obesity and insulin resistance. We posit that epigenetic programming during vulnerable periods of development (e.g. in utero or early childhood) is particularly prone to irreversible changes in the epigenome and the persistence of IR. This project will leverage access to state-of- the-art ambient exposure facilities, investigatie expertise in exposure science, disease pathways and epigenetics available at the University of Maryland and Johns Hopkins University to accomplish these specific aims. SA1: To characterize the epigenomic changes in response to air pollution that may either precede or overlap with the development of an insulin resistant phenotype. SA2: To define the IR and global epigenomic changes associated with early life CAP exposures. SA3: To determine whether cessation of air pollution exposure reverses insulin resistance and corresponding epigenomic changes. SA4: To integrate the epigenomic and transcriptomic perturbations that track with the development of the IR phenotype. These animal model studies with our well optimized controlled air pollution exposure that cause metabolic syndrome will reveal comprehensive epigenomic marks that precede the phenotype and are conserved between the target and surrogate tissues. The data will provide new leads for validation of mechanisms as well insight into interpretation of human studies.