Role of miRNAs in the transmission of metabolic risks

miRNA 在代谢风险传递中的作用

• 批准号: 10446558
• 负责人: Alexander K. Murashov
• 金额: $ 37.92万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446558
• 关键词: Adopted; Adverse effects; Affect; Animal Model; Biochemical; Bioenergetics; Brain; Calories; Cells; Child; Chronic; Closure by clamp; Complex; Consumption; Data; Development; Drosophila genus; Early Diagnosis; Eating; Energy Metabolism; Environmental Risk Factor; Epigenetic Process; Exercise; Family; Fat Body; Feeding behaviors; Female; Future; Generations; Genetic; Germ Cells; Glucose Intolerance; Heritability; High Fat Diet; Human; Impairment; In Vitro; Inherited; Intervention; Knowledge; Laboratories; Lead; Longevity; Metabolic; Metabolic Diseases; Metabolic dysfunction; Methodology; MicroRNAs; Mission; Mitochondria; Modeling; Molecular; Molecular Target; Monitor; Motor Activity; Muscle; Obesity; Obesity Epidemic; Phenotype; Physiological; Play; Pliability; Predisposition; Proteome; Proteomics; Public Health; Publishing; Research; Resolution; Risk; Role; Somatic Cell; Techniques; Testing; Tissues; United States National Institutes of Health; base; diet and exercise; fly; genome-wide; in vivo; innovation; insight; knowledge base; male; metabolic phenotype; miRNA expression profiling; mitochondrial dysfunction; molecular marker; mortality; mouse model; multiplex assay; novel; novel diagnostics; novel therapeutic intervention; nutrition; obesity in children; offspring; personalized intervention; sedentary; sperm cell; transcriptome sequencing; transcriptomics; transgenerational epigenetic inheritance; transmission process; western diet

The childhood obesity epidemic has been strongly associated with environmental factors. Family aggregation studies in humans and transgenerational studies in animal models show that obesity is highly heritable, and ancestral exposures can predispose offspring to the risk of various metabolic disorders. Our laboratory was the first to show the role of paternal exercise in programming “thrifty phenotype” in offspring. Our published and preliminary OXPHOS efficiency analyses using Drosophila and mouse models indicate that the “thrifty phenotype” is caused by an alteration in the offspring's mitochondrial bioenergetic efficiency. Preliminary proteomic and transcriptomic analyses revealed that developmental changes in bioenergetic efficiency were due to mitochondrial proteome remodeling associated with alterations in somatic and germ cell microRNAs (miRNAs), thereby providing a potential mechanism for the transgenerational transmission and programming of metabolic risks. The central hypothesis of the project is that miRNAs play a key role in the developmental programming of mitochondrial bioenergetic efficiency. Based on published and preliminary data, a secondary hypothesis is that changes in mitochondrial bioenergetic efficiency are inherited via spermatozoal cells as alterations in miRNAs. To test these hypotheses, we propose to take advantage of the physiological simplicity and genetic manipulability of fruit fly Drosophila. Therefore, the specific aims for this project are: Aim 1. Determine the functional consequences of altered miRNA expression in programming offspring metabolic state. Aim 2. Determine the spermatozoal epimutations responsible for the transgenerational programming of the bioenergetic phenotype. The methodological innovations of this project include the application of a multiplexed assay platform with a variable energetic clamp technique recently adopted to flies, a novel proteomics-based approach to merge mitochondrial flux data with in-house proteomics to reveal molecular markers of transgenerational phenotype. This study is expected to significantly advance our understanding of the epigenetic origins of childhood obesity. Deciphering primary molecular mechanisms of developmental metabolic programming will provide a better understanding of how childhood obesity and related metabolic diseases could be more effectively targeted.

儿童肥胖的流行与环境因素密切相关。人类的家庭聚集研究和动物模型的跨代研究表明，肥胖具有高度遗传性，祖先的肥胖可能使后代易患各种代谢紊乱的风险。研究人员利用果蝇和小鼠模型进行了已发表的初步 OXPHOS 效率分析，表明父系锻炼在后代“节俭表型”编程中的作用表明，“节俭表型”是由基因的改变引起的。后代的线粒体生物能效率。 初步的蛋白质组学和转录组学分析表明，生物能效率的发育变化是由于与体细胞和生殖细胞 microRNA (miRNA) 的改变相关的线粒体蛋白质组重塑，从而为代谢风险的跨代传递和编程提供了潜在的机制。该项目认为 miRNA 在线粒体生物能效率的发育编程中发挥着关键作用，基于已发表的初步数据，第二个假设是线粒体生物能效率的变化为了测试这些假设，我们建议利用果蝇的生理简单性和遗传可操作性，因此，该项目的具体目标是： 目标 1. 确定子代代谢状态中 miRNA 编程表达改变的功能后果。 目标 2. 确定负责生物能量表型跨代编程的精子表突变。 该项目的方法创新包括应用最近在果蝇中采用的具有可变能量钳测定技术的多重平台，这是一种基于蛋白质组学的新颖方法，将线粒体通量数据与内部蛋白质组学合并，以揭示跨代表型研究的分子标记。预计将显着增进我们对儿童肥胖表观遗传起源的理解，破译发育代谢编程的主要分子机制将有助于更好地了解如何更有效地针对儿童肥胖和相关代谢疾病。