DNA Methylation and Vascular Function in Obesity: Role of Exercise and Weight Loss

项目摘要/摘要 这项研究的长期目标是确定有效的目标和战略，以预防和治疗 肥胖相关的心血管疾病。肥胖的特征是脂肪组织大量堆积， 分泌多种炎症介质(称为脂肪细胞因子)，产生全身炎症状态。 这些脂肪细胞因子导致血管功能障碍，这是发展心血管疾病的第一步 疾病。肥胖受饮食和体力活动等环境因素的影响。这些因素导致 表观遗传变化，即在不改变DNA序列的情况下影响基因表达的变化。其中之一 这些表观遗传修饰是DNA甲基化(称为低甲基化)的减少，导致 随后基因表达的增加。我们的初步研究表明，从脂肪中提取的DNA 与非肥胖对照组相比，肥胖受试者的组织甲基化程度较低。DNA低甲基化相关 肥胖者脂肪细胞因子表达明显增加，血管扩张功能受损。因此， 我们假设肥胖成年人脂肪细胞因子表达的增加是由DNA介导的 DNA低甲基化和DNA低甲基化是预防肥胖相关炎症的有希望的靶点 和血管功能障碍。DNA甲基化的灵活可变性使其成为生活方式的完美目标 体力活动和减肥等干预措施。因此，我们建议有氧运动训练和举重 减肥手术后的丢失将逆转肥胖患者DNA低甲基化并改善血管功能 研究对象。我们将通过(1)研究脂肪细胞因子的异常DNA甲基化模式来检验我们的假设 在18至50岁肥胖成年人的脂肪组织中与非肥胖受试者进行比较；(2)测试 12周有氧运动对逆转DNA低甲基化及改善血管的作用 肥胖成年人的功能；以及(3)检查减肥手术对DNA甲基化和 血管功能。拟议的研究将提高我们对表观遗传学基础的理解。 肥胖相关血管功能障碍，寻找改善肥胖者血管功能的新治疗靶点 并为有氧运动训练和减肥的积极作用提供了证据 预防和治疗肥胖相关的心血管疾病。这些研究将产生积极的影响 关于加强肥胖相关心血管疾病的预防和治疗管理 影响着全球数百万人。因此，我们提出了有针对性的职业发展培训计划 其中申请者将接受负责任的临床研究行为培训，学习如何在各个方面 启动、实施和管理临床研究，以及如何高效地领导临床研究团队。通过完成 建议的培训(K99)，申请者将获得将提供初始步骤的知识和技能 在接下来的阶段(R00)走向她的科学自主性，她将处于过渡的有利地位 成功地从博士后实习生的角色转变为独立研究员的角色。

PROJECT SUMMARY/ABSTRACT The long-term goal of this study is to identify valid targets and strategies for the prevention and treatment of obesity-related cardiovascular disease. Obesity is characterized by a large accumulation of fat tissues that secrete numerous inflammatory mediators (called adipocytokines), generating a systemic inflammatory state. These adipocytokines induce vascular dysfunction which is the initial step towards developing cardiovascular disease. Obesity is affected by environmental factors such as diet and physical activity. These factors induce epigenetic changes, which are changes that affect gene expression without altering the DNA sequence. One of these epigenetic modifications is the reduction in DNA methylation (referred to as hypomethylation) resulting in subsequent increases in gene expression. Our preliminary studies showed that the extracted DNA from fat tissues of obese subjects is hypomethylated compared to non-obese controls. DNA hypomethylation correlated significantly with higher expression of adipocytokines and impaired vasodilation in obese subjects. Therefore, we hypothesize that the increase in adipocytokine expression in obese adults is mediated by DNA hypomethylation and that DNA hypomethylation is a promising target to prevent obesity-associated inflammation and vascular dysfunction. The flexible modifiable nature of DNA methylation makes it a perfect target for life style interventions such as physical activity and weigh loss. Thus, we propose that aerobic exercise training and weight loss following Bariatric surgery will reverse DNA hypomethylation and improve vascular function in obese subjects. We will test our hypotheses by (1) Investigating abnormal DNA methylation patterns of adipocytokines in fat tissues from obese adults between the age of 18 and 50 compared to non-obese subjects; (2) Test the effectiveness of 12-week aerobic exercise training on reversing DNA hypomethylation and improving vascular function in obese adults; and (3) Examine the effectiveness of weight loss surgery on DNA methylation and vascular function. The proposed studies will improve our understanding of the epigenetic underpinning of obesity-related vascular dysfunction, identify novel therapeutic targets for improving vascular function in obese adults, and provide an evidence for the positive effects of aerobic exercise training and weight loss on the prevention and treatment of obesity-associated cardiovascular disease. These studies will have a positive impact on improving the prevention and therapeutic management of obesity-related cardiovascular morbidities that affect millions of people worldwide. Therefore, we propose a focused career development training plan during which the applicant will be trained in the responsible conduct of clinical research, learn all aspects of how to start, implement and manage a clinical study and how to lead a clinical research team, efficiently. By completing the proposed training (K99), the applicant will obtain the knowledge and skills that will provide the initial steps towards her scientific autonomy in the subsequent phase (R00) and she will be well positioned to transition successfully from the role of a postdoctoral trainee to that of an independent researcher.