Epigenomics of Air Pollution driven Inflammation, Obesity and Insulin Resistance

空气污染引起的炎症、肥胖和胰岛素抵抗的表观基因组学

基本信息

批准号：
9275991
负责人：
Shyam Biswal
金额：
$ 56.23万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275991
关键词：
Adipose tissue Adult Age Air Air Pollution Airborne Particulate Matter Animal Model Blood Cells Blood Circulation Brown Fat C57BL/6 Mouse Cells Collection DNA Methylation Data Defect Development Diabetes Mellitus Diet Disease Disease Pathway Dose Environmental Risk Factor Epidemic Epigenetic Process Exposure to Fibrinogen Gene Expression Genes Glucose tolerance test Hepatic High Fat Diet Human Hypothalamic structure Inflammation Insulin Insulin Resistance Life Liver Maryland Mediating Metabolic Metabolic syndrome Methylation Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Particulate Pathway interactions Pattern Peripheral Phenotype Play Pollution Positioning Attribute Postpartum Period Predisposition Pregnancy Prevalence Prospective cohort study Reactive Oxygen Species Retrospective cohort Risk Factors Role Science Secondary to Skeletal Muscle Study models Testing Time Tissues Universities Urbanization Validation Visceral air filter air pollution control ambient air pollution bisulfite sequencing comparative early childhood early life exposure endoplasmic reticulum stress epidemiology study epigenome epigenomics genome-wide glycemic control histone modification immune function in utero insight insulin signaling insulin tolerance intrapartum monocyte mouse model promoter public health relevance response transcriptome sequencing transcriptomics young adult

项目摘要

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.

描述（由适用提供）：肥胖和II型糖尿病（T2D）在流行比例的情况下在全球范围内增加。流行病学研究表明空气污染是胰岛素抵抗（IR）和T2D发展的环境风险因素。但是，空气污染暴露导致渐进性IR导致T2D的机制尚不清楚。有越来越多的证据表明，通常在T2D之前经过数十年之前的IR可以通过表观遗传学变化来调节IR。妊娠和幼儿期是增强空气污染脆弱性的时期，也与首先建立表观遗传模式的阶段相吻合。 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 immunology function (hypothalamus, circulation and adipose), reduced brown adipose tissue function, hepatitic endoplasmic reticulum stress/steatosis and胰岛素反应组织中的胰岛素信号传导中的原型缺陷，例如肝脏，骨骼肌和脂肪。我们进一步证明，幼儿是一个脆弱时期，因为在此期间接触CAP会加速IR的发育，而在<10周内发生血糖控制的明显变化。此外，这些缺陷是反应性氧（ROS）途径（ROS）途径和胰岛素反应性组织中炎症的关键改变的继发性。盖帽暴露还会导致全基因组在5-MC中增加。假设：空气污染的暴露导致全球表观遗传学改变，导致目标时机重新编程，从而导致肥胖和胰岛素抵抗。我们肯定的是，在脆弱的发展时期（例如，在子宫或幼儿期）的表观遗传编程特别容易发生表观遗传组的不可逆转变化和IR的持久性。该项目将利用访问最新的环境风险设施，在曝光科学方面的调查专业知识，疾病途径和马里兰州大学和约翰·霍普金斯大学提供的专业知识，以实现这些特定目标。 SA1：表征响应于空气污染的表观基因组变化，该空气污染可能与胰岛素耐药表型的发展或重叠。 SA2：定义与早期生命上限暴露相关的IR和全球表观基因组变化。 SA3：确定停止空气污染暴露是否会逆转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组扰动。这些动物模型研究通过我们优化的受控空气污染暴露，导致代谢综合征将揭示出在表型之前的全面表观基因组痕迹，并且在靶标和替代组织之间是保守的。数据将为验证机制以及对人类研究解释的洞察力提供新的潜在客户。