Maternal nutrition and oocyte programming

孕产妇营养和卵母细胞编程

• 批准号: 9430774
• 负责人: KELLE H MOLEY
• 金额: $ 9.52万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-07 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9430774
• 关键词: 1 year old; Adipocytes; Adult; Affect; Age; Behavior Therapy; Behavioral; Body fat; Child; Cholesterol; Citric Acid Cycle; Complications of Diabetes Mellitus; DNA; DNA copy number; Data; Defect; Development; Developmental Delay Disorders; Diabetes Mellitus; Diet; Dietary Intervention; Disease; Epidemic; Epigenetic Process; Etiology; Event; Exercise; Fertilization; Functional disorder; Generations; Germ Cells; Glucose Intolerance; Goals; Health; High Fat Diet; Hypertension; Impairment; Infertility; Intellectual functioning disability; Intervention; Lead; Left; Link; Liver diseases; Metabolic; Metabolic Diseases; Metabolic syndrome; Methylation; Mitochondria; Mitochondrial DNA; Modification; Morphology; Mothers; Mouse Strains; Mus; Muscle Cells; Nature; Nuclear; Obese Mice; Obesity; Oocytes; Outcome; Pathway interactions; Phenotype; Pregnancy; Proteins; Publishing; Recommendation; Recycling; Reporting; Research Personnel; Role; Severities; Techniques; Testing; Therapeutic; Time; Treatment Efficacy; United States; Weaning; Weight; Woman; Work; autism spectrum disorder; base; cardiovascular disorder risk; experience; experimental study; feeding; global health; innovation; maternal obesity; mitochondrial dysfunction; mitochondrial metabolism; mother nutrition; mouse model; next generation; offspring; parkin gene/protein; pregnant; prevent; programs; promoter; public health relevance; reproductive; reproductive function; transmission process

 DESCRIPTION (provided by applicant): Obesity currently affects over one-third of reproductive-age women in the United States leading to overall health and metabolic disorders, including reproductive function. Obese women experience subfertility and infertility at greater rates but more importantly, when they do get pregnant, their offspring suffer significant health consequences. Offspring of obese women are more likely than those born to normal-weight women to be obese at one year of age; to have metabolic syndrome, hypertension, and liver disease as young children; and to experience developmental delay, intellectual disabilities, and autism spectrum disorder. Given the severity and intractability of the obesity epidemic, we must identify effective means of intervention to prevent these detrimental effects of maternal obesity; this requires determination of the underlying mechanisms. In this proposal, we plan to determine how maternal diet-induced obesity affects offspring in the next generation via oocyte programming. In Aim 1, we plan to examine if and how metabolic changes in TCA cycle components in the oocyte lead to mitophagic dysregulation. We will establish a timetable for this oocyte phenomenon and then determine how each of these steps manifests in the offspring. By triggering, inhibiting and replacing missing parts of mitophagy in the oocyte we hope to delineate the role of this pathway in normal and abnormal oocytes. Finally, using different mouse strains we will distinguish paternal from maternal mtDNA and determine if elimination of paternal mitochondrial is perturbed. In Aim 2, we tackle the question of whether the transmission to offspring is nuclear or mitochondrial in origin. Using the unique expertise of two key Co- Investigators, we will discern if epigenetic modifications, nuclear or mitochondrial, are occurring. Also using the reciprocal techniques of ST and CT we will determine which cellular constituent is responsible for the phenotype. Finally, using the same dual strain experiments used in Aim 1, we will answer the important question of the origin of the offspring "bad" mitochondria-left over or newly made. In Aim 3, we test the possibility that maternal interventions, specifically exercise and dietary changes, can reverse or rescue these events and offspring outcomes. If successful, these findings will greatly enhance our understanding of developmental origins of disease and will have implications for not only the timing, but also the nature, of effective therapeutic and behavioral recommendations for reproductive-age women.

 描述（由申请人提供）：肥胖目前影响着美国三分之一以上的育龄妇女，导致整体健康和代谢紊乱，包括生殖功能。肥胖女性出现生育能力低下和不孕的几率更高，但更重要的是，当她们怀孕时，她们的后代会遭受严重的健康后果。肥胖女性的后代比正常体重女性所生的后代在一岁时肥胖的可能性更大；幼儿时患有代谢综合征、高血压和肝病；并经历发育迟缓、智力障碍和自闭症谱系障碍。鉴于肥胖流行病的严重性和棘手性，我们必须找到有效的干预手段来预防孕产妇肥胖的这些有害影响；这需要确定根本机制。在这项提案中，我们计划通过卵母细胞编程确定母亲饮食引起的肥胖如何影响下一代后代。在目标 1 中，我们计划检查卵母细胞中 TCA 循环成分的代谢变化是否以及如何导致线粒体自噬失调。我们将为这种卵母细胞现象制定一个时间表，然后确定每个步骤如何在后代中体现。通过触发、抑制和替换卵母细胞中线粒体自噬的缺失部分，我们希望描述该途径在正常和异常卵母细胞中的作用。最后，使用不同的小鼠品系，我们将区分父本线粒体 DNA 和母本线粒体 DNA，并确定父本线粒体的消除是否受到干扰。在目标 2 中，我们解决了遗传给后代的问题是起源于核还是线粒体。利用两位关键联合研究人员的独特专业知识，我们将辨别是否正在发生表观遗传修饰（核或线粒体）。我们还利用 ST 和 CT 的相互技术来确定哪种细胞成分导致了表型。最后，使用目标 1 中使用的相同双菌株实验，我们将回答后代“坏”线粒体（遗留的或新产生的）起源的重要问题。在目标 3 中，我们测试了母亲干预措施（特别是运动和饮食改变）可以逆转或挽救这些事件和后代结果的可能性。如果成功，这些发现将极大地增强我们对疾病发育起源的理解，不仅对育龄妇女有效治疗和行为建议的时机，而且对其性质产生影响。