Epigenomics of Air Pollution driven Inflammation, Obesity and Insulin Resistance

 描述(申请人提供)：肥胖和II型糖尿病(T2D)在全球范围内一直在以流行的比例增加。流行病学研究表明，空气污染是 导致胰岛素抵抗(IR)和T2D的环境危险因素。然而，空气污染暴露导致进行性IR导致T2D的机制尚不清楚。越来越多的证据表明，IR通常比T2D早几十年，可能是通过表观遗传变化来调节的。妊娠期和幼儿期是易受空气污染影响的时期，也与表观遗传模式首次建立的阶段不谋而合。我们之前已经在小鼠模型中建立了这样的模型：暴露于高浓度环境污染(CAP；12周)会加剧肥胖、IR和T2D的发展，并诱导一系列典型的IR和T2D异常，包括全身组织(下丘脑、循环和脂肪)免疫功能的变化，棕色脂肪组织功能降低，肝脏内质网应激/脂肪变性，以及胰岛素反应组织(如肝脏、骨骼肌和脂肪)胰岛素信号典型缺陷。我们进一步证明，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，并在10周内发生明显的血糖控制变化。此外，这些缺陷是继发于活性氧簇(ROS)途径的严重变化和胰岛素反应组织中的炎症。CAP暴露还会导致全基因组内5-MC的增加。假设：空气污染暴露会导致全球表观遗传改变，导致目标组织的代谢重新编程，从而导致肥胖和胰岛素抵抗。我们假设，在发育的脆弱时期(例如，在子宫或儿童早期)，表观遗传编程特别容易发生不可逆的表观基因组变化和IR的持久性。该项目将利用马里兰大学和约翰·霍普金斯大学提供的最先进的环境暴露设施、暴露科学方面的调查专业知识、疾病途径和表观遗传学来实现这些具体目标。SA1：描述响应空气污染的表观基因组变化，这些变化可能先于或与胰岛素抵抗表型的发展重叠。SA2：定义与早期生命CAP暴露相关的IR和全球表观基因组变化。SA3：确定停止空气污染暴露是否逆转了胰岛素抵抗和相应的表观基因组变化。SA4：整合跟踪IR表型发展的表观基因组和转录扰动。这些动物模型研究通过我们良好优化的可控空气污染暴露导致代谢综合征，将揭示在表型之前且在靶组织和替代组织之间保守的全面的表观基因组标记。这些数据将为机制的验证以及对人体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.