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

• 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
• 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

 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 胰岛素抵抗 (IR) 和 T2D 发展的环境危险因素。然而，空气污染暴露导致进行性 IR 导致 T2D 的机制仍不清楚。越来越多的证据表明，IR 通常先于 T2D 数十年，可能通过表观遗传变化进行调节。妊娠期和幼儿期是最容易受到空气污染影响的时期，也是表观遗传模式首次建立的阶段。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 周会加剧肥胖、IR 和 T2D 的发展，并且还会诱发一系列 IR 和 T2D 典型的异常，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 应激/脂肪变性以及胰岛素反应组织（如肝脏、骨骼肌和脂肪）中胰岛素信号传导的典型缺陷。我们进一步证明，早年是一个脆弱时期，因为在此期间接触 CAP 会加速 IR 的发展，并在 10 周内出现血糖控制的明显变化。此外，这些缺陷是活性氧（ROS）途径的关键改变和胰岛素反应组织炎症的继发因素。 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全球表观遗传改变，从而导致目标组织代谢重新编程，从而导致肥胖和胰岛素抵抗。我们假设，在发育的脆弱时期（例如在子宫内或幼儿期），表观遗传编程特别容易发生表观基因组不可逆转的变化和 IR 的持续存在。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、疾病途径和表观遗传学方面的研究专业知识来实现​​这些具体目标。 SA1：表征因空气污染而发生的表观基因组变化，这些变化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。 SA2：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可以逆转胰岛素抵抗和相应的表观基因组变化。 SA4：整合与 IR 表型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。这些数据将为验证机制以及解释人类研究提供新的线索。