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

DNA 甲基化和肥胖中的血管功能：运动和减肥的作用

• 批准号: 10227087
• 负责人: Abeer M Mohamed
• 金额: $ 24.56万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227087
• 关键词: Aberrant DNA Methylation; Adipocytes; Adipose tissue; Aerobic Exercise; Affect; Age; Anti-Inflammatory Agents; Antioxidants; Autoimmune Diseases; Bariatrics; Biological Assay; Biological Markers; Biopsy; Blood Vessels; Body Weight decreased; Cardiovascular Diseases; Cardiovascular system; ChIP-seq; Clinical Research; DNA; DNA Methylation; DNA Sequence; Data; Diabetes Mellitus; Diet; Effectiveness; Endocrine; Environmental Risk Factor; Epigenetic Process; Event; Exercise; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Homeostasis; Hypoxia; Hypoxia Inducible Factor; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-6; Knowledge; Lead; Learning; Leptin; Link; Malignant Neoplasms; Measurement; Measures; Mediating; Methylation; Microvascular Dysfunction; Modification; Molecular; Morbidity - disease rate; Nature; Nitric Oxide; Non obese; Obesity; Obesity associated cardiovascular disease; Operative Surgical Procedures; Pathway interactions; Phase; Physical activity; Physiologic pulse; Positioning Attribute; Predisposing Factor; Prevention; Prevention strategy; Preventive; Process; Production; Proteins; Randomized; Research; Research Personnel; Resistance; Role; Sampling; Testing; Therapeutic; Therapeutic Intervention; Thinness; Tissues; Training; Vascular Diseases; Vascular System; Vasodilation; Visceral; adipokines; adult obesity; arteriole; bariatric surgery; base; career development; comorbidity; cytokine; demethylation; effectiveness testing; endothelial dysfunction; environmental change; exercise training; flexibility; hypoxia inducible factor 1; improved; in vivo; lifestyle intervention; methylation pattern; new therapeutic target; obese person; obesity management; obesity prevention; obesity treatment; promoter; recruit; skills; social; subcutaneous; therapeutic target

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.

项目总结/摘要 本研究的长期目标是确定有效的目标和策略，以预防和治疗 肥胖相关的心血管疾病肥胖症的特征是脂肪组织大量堆积， 分泌大量炎症介质（称为脂肪细胞因子），产生全身性炎症状态。 这些脂肪细胞因子诱导血管功能障碍，这是发展心血管疾病的第一步。 疾病肥胖受环境因素如饮食和体力活动的影响。这些因素导致 表观遗传变化，即影响基因表达而不改变DNA序列的变化。之一 这些表观遗传修饰是DNA甲基化的减少（称为低甲基化）， 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 与非肥胖对照相比，肥胖受试者的组织是低甲基化的。DNA低甲基化相关 在肥胖受试者中，脂肪细胞因子的表达显著升高，血管舒张受损。因此，我们认为， 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， 低甲基化和DNA低甲基化是预防肥胖相关炎症有希望的靶点 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 干预措施，如体育活动和减肥。因此，我们建议有氧运动训练和体重 减肥手术后的损失将逆转DNA低甲基化并改善肥胖患者的血管功能。 科目我们将通过（1）研究脂肪细胞因子的异常DNA甲基化模式来验证我们的假设 与非肥胖受试者相比，在来自18至50岁之间的肥胖成年人的脂肪组织中;（2）测试 12周有氧运动对逆转DNA低甲基化和改善血管内皮细胞功能的影响 功能在肥胖的成年人;和（3）检查减肥手术对DNA甲基化的有效性， 血管功能拟议的研究将提高我们对表观遗传基础的理解， 肥胖相关的血管功能障碍，确定改善肥胖患者血管功能的新治疗靶点 成年人，并提供证据的积极影响有氧运动训练和减肥的 预防和治疗肥胖相关的心血管疾病。这些研究将产生积极影响 关于改善肥胖相关心血管疾病的预防和治疗管理， 影响着全世界数百万人因此，我们提出了一个有针对性的职业发展培训计划， 申请人将接受临床研究负责任行为的培训，学习如何 启动，实施和管理临床研究，以及如何有效地领导临床研究团队。通过完成 建议的培训（K99），申请人将获得的知识和技能，将提供初始步骤 在随后的阶段（R 00），她将很好地过渡到她的科学自主权。 成功地从一个博士后实习生的角色，一个独立的研究人员。

项目成果

An Overview of Epigenetics in Obesity: The Role of Lifestyle and Therapeutic Interventions.

• DOI: 10.3390/ijms23031341
• 发表时间: 2022-01-25
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Mahmoud AM

Obesity-Associated Vitamin D Deficiency Correlates with Adipose Tissue DNA Hypomethylation, Inflammation, and Vascular Dysfunction.

• DOI: 10.3390/ijms232214377
• 发表时间: 2022-11-19
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Genetic Variation and Immunohistochemical Localization of the Glucocorticoid Receptor in Breast Cancer Cases from the Breast Cancer Care in Chicago Cohort.

• DOI: 10.3390/cancers13102261
• 发表时间: 2021-05-13
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Al-Alem U;Mahmoud AM;Batai K;Shah-Williams E;Gann PH;Kittles R;Rauscher GH
• 通讯作者: Rauscher GH

CD147 Levels in Blood and Adipose Tissues Correlate with Vascular Dysfunction in Obese Diabetic Adults.

血液和脂肪组织的CD147水平与肥胖糖尿病成年人的血管功能障碍相关。

• DOI: 10.3390/jcdd9010007
• 发表时间: 2021-12-28
• 期刊: Journal of cardiovascular development and disease
• 影响因子: 2.4
• 作者: Ali MM;Mirza I;Naquiallah D;Hassan C;Masrur M;Bianco FM;Mahmoud AM
• 通讯作者: Mahmoud AM

Adipose Tissue Hypoxia Correlates with Adipokine Hypomethylation and Vascular Dysfunction.

• DOI: 10.3390/biomedicines9081034
• 发表时间: 2021-08-18
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Ali MM;Hassan C;Masrur M;Bianco FM;Naquiallah D;Mirza I;Frederick P;Fernandes ET;Giulianotti CP;Gangemi A;Phillips SA;Mahmoud AM
• 通讯作者: Mahmoud AM