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：
9098288
负责人：
Shyam Biswal
金额：
$ 55.66万
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/9098288
关键词：
Adipose tissue Adult Age Air Air Pollution Animal Model Blood Cells Blood Circulation Brown Fat C57BL/6 Mouse Cells Cohort Studies Collection DNA Methylation Data Defect Development Diabetes Mellitus Diet Disease Disease Pathway Dose Environmental Risk Factor Epidemic Epidemiologic Studies Epigenetic Process Exposure to Gene Expression Genes Glucose tolerance test Hepatic High Fat Diet Human Hypothalamic structure Inflammation Insulin Insulin Resistance Life Liver Maps 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 Reactive Oxygen Species Risk Factors Role Science Secondary to Skeletal Muscle Staging 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 epigenome epigenomics genome-wide glycemic control histone modification immune function in utero insight insulin signaling insulin tolerance monocyte mouse model programs promoter prospective 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（由申请人提供）：肥胖和 II 型糖尿病 (T2D) 在全球范围内呈流行趋势，流行病学研究表明，空气污染正在加剧。胰岛素抵抗 (IR) 和 T2D 的环境风险因素然而，空气污染导致 IR 导致 T2D 的机制仍不清楚。越来越多的证据表明，IR 可能比 T2D 早发生数十年。妊娠期和幼儿期是对空气污染的脆弱性增强的时期，也与表观遗传模式首次建立的阶段一致，我们之前在小鼠模型中建立了集中环境污染（CAP）暴露超过 12 周的阶段。加剧肥胖、IR和T2D的发展，并诱导一系列IR和T2D的典型异常，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、肝内质网我们进一步证明，早年是一个时期。脆弱性，因为在此期间暴露于 CAP 会加速 IR 的发展，并在不到 10 周内血糖控制发生明显变化。此外，这些缺陷是活性氧 (ROS) 途径和胰岛素反应组织炎症的关键改变的继发因素。 CAP 暴露还会导致全基因组 5-mC 增加。假设：空气污染暴露会导致整体表观遗传改变，从而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。发育时期（例如在子宫内或幼儿期）特别容易发生表观基因组不可逆转的变化和 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、疾病方面的研究专业知识。马里兰大学和约翰霍普金斯大学可利用的途径和表观遗传学来实现这些特定目标 SA1：表征可能先于或与胰岛素抵抗表型的发展重叠的表观基因组变化。定义与生命早期 CAP 暴露相关的 IR 和整体表观基因组变化 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：整合与 IR 发展相关的表观基因组和转录组扰动。这些动物模型研究采用我们精心优化的受控空气污染暴露引起的代谢综合征，将揭示先于表型并在目标组织和替代组织之间保守的全面表观基因组标记，这些数据将为研究提供新的线索。机制验证以及对人类研究解释的洞察。