Epigenetic Basis of Obesity Induced Cardiovascular Disease and Type 2 Diabetes

肥胖诱发的心血管疾病和 2 型糖尿病的表观遗传学基础

• 批准号: 8023366
• 负责人: XIAOLING WANG
• 金额: $ 59.48万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8023366
• 关键词: 11 year old; Adipose tissue; Adult; Aerobic Exercise; African American; Age; Attention; Biological Assay; Blood Pressure; Body Weight decreased; Cardiovascular Diseases; Cardiovascular system; Caucasians; Caucasoid Race; Cell Line; Cells; Child; Collecting Cell; Comorbidity; DNA; DNA Methylation; DNA Methyltransferase Inhibitor; Defect; Disease; Epidemic; Epigenetic Process; Equilibrium; Ethnic Origin; Exercise; Female; Funding; Future; Gender; Gene Expression; Genes; Goals; Health; Healthcare; Immune System Diseases; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Intervention; Life; Lipids; Measures; Mediating; Mediation; Metabolic; Methylation; Modeling; Molecular; Mononuclear; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Participant; Pathogenesis; Pathway interactions; Peripheral Blood Mononuclear Cell; Physiologic pulse; Population; Prevention; Prevention approach; Prevention therapy; Preventive Health Services; Process; RNA; Randomized; Regulation; Research; Resolution; Risk; Risk Factors; Sampling; Site; Staging; Techniques; Testing; Thick; Time; United States National Institutes of Health; Validation; Work; adipokines; aged; base; body system; cardiovascular disorder risk; cytokine; demethylation; diabetes risk; diabetic; early onset; genome wide association study; immune function; intervention program; intima media; male; middle age; peripheral blood; research study; response

DESCRIPTION (provided by applicant): Obesity is associated with numerous comorbidities such cardiovascular diseases (CVD) and type 2 diabetes (T2D). The common denominator in the pathogenesis of the co-morbidities of obesity is the presence of an active, low-grade inflammatory process. In context of the recently emerging evidence on the importance of epigenetic regulation in the immune and inflammatory responses, we hypothesize that obesity induced defects in immune function is caused, at least in part, by DNA methylation changes in peripheral blood mononuclear cells in response to adipokines and cytokines secreted by adipose tissue. Based on our preliminary studies which provided strong support to this hypothesis, we aim to identify the differential methylation profiles between obese cases and lean controls and further evaluate whether these methylation changes are involved in the pathogenesis of obesity related co-morbidities. First, we will identify the CpG sites where DNA methylation differs between obese cases and lean controls employing a step-wise selection process involving 2 stages (Aim 1). After interrogation of 27,000 methylation sites in more than 14,000 genes in 100 obese cases and 100 lean controls, we will choose the most promising for validation in a subsequent stage with 300 obese cases and 300 lean controls eventually leading to the (approximately) 20 most likely/important sites. Next, we will determine the potential downstream mechanisms of DNA methylation differences on gene expression (Aim 2) by assessing whether changes in methylation of these CpG sites are associated with changes in gene expression in the cells collected from aim 1. Functional in vitro experiments will also be conducted to investigate whether demethylation of these CpG sites can activate gene expression. Furthermore, we will determine whether the effect of obesity on CVD and T2D risk factors is -at least partially- mediated by the methylation changes of these CpG sites in a total of 1600 subjects (Aim 3). Secondary specific aims will test (1) whether the above relationships are ethnicity and/or gender dependent; (2) whether 8-month aerobic exercise intervention in overweight children will change the methylation status of these differential methylation sites. Identification of methylation changes in specific genes in obesity will provide important targets for further study into the mechanisms of obesity's effect on the immune system and the potential to develop new therapies to treat multiple obesity comorbidities independent of weight loss. PUBLIC HEALTH RELEVANCE: Obesity is becoming a global epidemic in both children and adults. Obesity dramatically increases the risk of many diseases such as cardiovascular disease and type 2 diabetes. This research aims to identify obesity induced epigenetic changes in the immune and inflammatory response and further evaluate whether these changes are associated with the risk of cardiovascular disease and type 2 diabetes. The identification of epigenetic changes in specific genes in obesity will provide important targets for developing new prevention approaches or therapies to treat multiple obesity co-morbidities.

描述（由申请人提供）：肥胖与许多合并症相关，如心血管疾病（CVD）和2型糖尿病（T2 D）。肥胖合并症发病机制的共同点是存在活跃的低度炎症过程。在最近出现的证据在免疫和炎症反应中的表观遗传调控的重要性的背景下，我们假设，肥胖诱导的免疫功能缺陷引起的，至少部分是由外周血单核细胞中的DNA甲基化的变化，响应脂肪组织分泌的脂肪因子和细胞因子。基于我们的初步研究，这提供了强有力的支持，这一假设，我们的目标是确定差异的甲基化模式之间的肥胖病例和瘦对照，并进一步评估这些甲基化的变化是否参与肥胖相关的共病的发病机制。首先，我们将采用涉及2个阶段的逐步选择过程来确定肥胖病例和瘦对照之间DNA甲基化不同的CpG位点（目的1）。在询问了100例肥胖病例和100例瘦对照的14，000多个基因中的27，000个甲基化位点后，我们将选择最有希望的位点进行验证，在随后的阶段，300例肥胖病例和300例瘦对照最终导致（大约）20个最可能/重要的位点。接下来，我们将通过评估这些CpG位点的甲基化变化是否与从目标1收集的细胞中的基因表达变化相关，来确定DNA甲基化差异对基因表达的潜在下游机制（目标2）。还将进行功能性体外实验以研究这些CpG位点的去甲基化是否可以激活基因表达。此外，我们将在总共1600名受试者中确定肥胖对CVD和T2 D风险因素的影响是否-至少部分-由这些CpG位点的甲基化变化介导（目标3）。第二个具体目标将测试（1）上述关系是否具有种族和/或性别依赖性;（2）超重儿童8个月的有氧运动干预是否会改变这些差异甲基化位点的甲基化状态。确定肥胖症中特定基因的甲基化变化将为进一步研究肥胖症对免疫系统的影响机制以及开发新疗法以治疗与体重减轻无关的多种肥胖症合并症的潜力提供重要靶点。 公共卫生相关性：肥胖正在成为儿童和成人的全球流行病。肥胖会显著增加患心血管疾病和2型糖尿病等多种疾病的风险。这项研究旨在确定肥胖引起的免疫和炎症反应的表观遗传变化，并进一步评估这些变化是否与心血管疾病和2型糖尿病的风险有关。确定肥胖症中特定基因的表观遗传变化将为开发新的预防方法或治疗多种肥胖症共病的疗法提供重要靶点。