Epigenetics of energy homeostasis, bioenergetics and obesity

能量稳态、生物能量学和肥胖的表观遗传学

• 批准号: 10164222
• 负责人: Melanie Carless
• 金额: $ 77.52万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164222
• 关键词: Adolescent; Adult; Affect; African American; Anthropometry; Atherosclerosis; Automobile Driving; Biochemical; Biochemistry; Bioenergetics; Biological Assay; Biological Models; Biological Process; Blood; Blood specimen; Body Composition; Body Size; Body Weight decreased; Body fat; CRISPR/Cas technology; Calorimetry; Candidate Disease Gene; Caucasians; Cell Line; Cell Respiration; Cell model; Cell physiology; Cells; Child; Childhood; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Complex; Consumption; DNA Methylation; Data; Derivation procedure; Development; Diet; Disease Progression; Eating Behavior; Economic Burden; Energy Intake; Energy Metabolism; Engineering; Environmental Risk Factor; Epigenetic Process; Equilibrium; Etiology; Expenditure; Fatty Acids; Gap Junctions; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Risk; Genome; Glycolysis; Goals; Health; Hispanics; Homeostasis; Hour; Human; Hypertension; In Vitro; Indirect Calorimetry; Individual; Lead; Link; Measures; Mediating; Medical; Metabolism; Methylation; Mission; Modification; Molecular; Molecular Target; Morbidity - disease rate; Muscle; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Onset of illness; Outcome; Outcomes Research; Pathogenesis; Pathway interactions; Phenotype; Physical Fitness; Physical activity; Physiological; Play; Population; Prevalence; Prevention; Prognostic Marker; Protons; Public Health; Relative Risks; Research; Research Design; Respiration; Risk; Risk Factors; Role; Sampling; Site; Skeletal Muscle; Stimulus; System; Technology; Testing; Therapeutic Intervention; Tissues; United States; United States National Institutes of Health; Validation; Variant; base; blood-based biomarker; cohort; critical period; design; diagnostic biomarker; diet and fitness; energy balance; epigenetic regulation; epigenome; experimental study; fatty acid oxidation; gene function; genome-wide; high risk; improved; in vitro Model; induced pluripotent stem cell; mortality; next generation sequencing; obesity development; obesity in children; obesity risk; obesity treatment; peripheral blood; population based; socioeconomics; success; targeted treatment

PROJECT SUMMARY Obesity is a chronic medical condition, defined by the accumulation of excess body fat and associated with high rates of morbidity and mortality. In the United States, obesity affects more than one-third of the adult population, and even more alarming, it affects about one-fifth of children and adolescents. Moreover, ethnic variations in obesity prevalence are evident, with rates in Hispanic children much higher than that of Caucasians. The obesity phenotype is essentially governed by energy homeostasis – the intricate balance between energy intake, energy expenditure and energy storage. The complex interplay of genetic and environmental insults leading to obesity are likely mediated through this energy nexus. The ultimate goal of this project is to identify epigenetic marks that might contribute to energy homeostasis and cellular bioenergetics, which culminate in obesity risk. Using state-of-the-art next-generation sequencing technologies we will examine DNA methylation profiles in a targeted-design assay that includes several hundred well justified candidate genes and more than a hundred thousand representative CpG loci across the genome. This application makes use of the Viva la Familia Study, designed to assess genetic and environmental risk factors for obesity development in Hispanic children. It provides a unique collection of phenotypes, including anthropometry and body composition, diet and physical fitness, 24-hour calorimetry data to assess energy expenditure, eating behavior, and blood biochemistries. 916 Hispanic children from this study will undergo blood-based DNA methylation profiling to identify associations with phenotypes related to energy intake and expenditure, and obesity. We will examine DNA methylation correlations in three cohorts of paired blood-muscle samples to prioritize genes for functional analysis. To understand how DNA methylation changes associated with energy phenotypes and obesity might influence energy utilization at a cellular level, we will employ an iPSC-derived skeletal muscle cell system. For three highly significant energy- and/or obesity-associated CpG sites or differentially methylated regions, we will investigate the effect of CRISPR- mediated epigenetic modifications on gene expression and bioenergetics. We will investigate effects on cellular basal and maximal respiration, ATP-linked respiration, proton leak, fatty acid utilization and glycolysis. By investigating the role of DNA methylation in energy-related phenotypes and cellular bioenergetics, we hope to further elucidate the epigenetic mechanisms contributing to obesity. The epigenome is in a constant state of flux and is not only modified by external environmental stimuli but can be edited through epigenetic engineering. The identification of genes involved in energy balance and obesity can provide a basis for the development of targeted therapies aimed at understanding gene function, and ultimately the treatment of obesity.

项目摘要 肥胖是一种慢性疾病，由多余的体内脂肪的积累定义 发病率和死亡率。在美国，肥胖会影响成年人口的三分之一以上， 更令人震惊的是，它影响了约五分之一的儿童和青少年。此外，种族变化 肥胖症患病率证明了，西班牙裔儿童的率高于高加索人。肥胖 表型基本上受能量稳态的控制 - 能量摄入，能量之间的复杂平衡 支出和能源存储。遗传和环境侮辱的复杂相互作用导致肥胖症 可能是通过这种能量联系介导的。该项目的最终目标是识别表观遗传标记 这可能有助于能量稳态和细胞生物能力学，这最终导致肥胖风险。 使用最新的下一代测序技术，我们将检查A中的DNA甲基化谱 有针对性的设计测定法，其中包括数百个合理的候选基因和一百多个 跨基因组的千名代表性CpG基因座。该应用利用了Viva la Familia研究， 旨在评估西班牙裔儿童肥胖发展的遗传和环境危险因素。 提供了独特的表型集合，包括人体测量法和身体成分，饮食和身体 健身，24小时的量热法数据，以评估能量消耗，饮食行为和血液生物学。 916 这项研究的西班牙裔儿童将经历基于血液的DNA甲基化分析，以识别与 与能量摄入和支出以及肥胖有关的表型。我们将检查DNA甲基化相关性 在三个配对的血液样品中，以优先考虑基因进行功能分析。了解如何 与能量表型和肥胖相关的DNA甲基化变化可能会影响能量利用 一个细胞水平，我们将采用IPSC衍生的骨骼肌细胞系统。对于三个高度重要的能量 和/或与肥胖相关的CpG部位或不同甲基化区域，我们将研究CRISPR-的影响 对基因表达和生物能学的介导的表观遗传修饰。我们将研究对细胞的影响 碱性和最大呼吸，ATP连接的呼吸，质子泄漏，脂肪酸利用和糖酵解。 通过研究DNA甲基化在能量相关表型和细胞生物能学中的作用，我们希望 进一步阐明造成肥胖的表观遗传机制。表观基因组处于恒定状态 通量不仅通过外部环境刺激来修饰，而且可以通过表观遗传学工程进行编辑。 识别涉及能量平衡和肥胖的基因可以为发展提供基础 旨在了解基因功能的靶向疗法，最终是肥胖的治疗方法。