Maternal nutrition and oocyte programming

孕产妇营养和卵母细胞编程

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：肥胖症目前影响美国超过三分之一的生殖年龄妇女，导致整体健康和代谢性疾病，包括生殖功能。肥胖的妇女以更大的速度经历了不育和不育，但更重要的是，当她们怀孕时，她们的后代会遭受重大的健康后果。肥胖妇女的后代比正常体重妇女在一岁时肥胖的后代更有可能。年幼的儿童患有代谢综合征，高血压和肝病；并体验发育延迟，智力障碍和自闭症谱系障碍。鉴于肥胖症流行的严重程度和顽固性，我们必须确定有效的干预手段，以防止孕产妇肥胖的这些有害影响。这需要确定基本机制。在这项建议中，我们计划确定孕产妇饮食引起的肥胖如何通过卵母细胞编程影响下一代的后代。在AIM 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导致线粒体失调。我们将为这种卵母细胞现象建立一个时间表，然后确定这些步骤中的每个步骤如何在后代中表现出来。通过触发，抑制和替换卵母细胞中线粒体缺失的部分，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，使用不同的小鼠菌株，我们将把父亲与母子mtDNA区分开，并确定是否消除了父亲的线粒体。在AIM 2中，我们解决了向后代的传播是核还是线粒体起源的问题。使用两个主要研究人员的独特专业知识，我们将辨别出表观遗传修饰（核或线粒体）是否发生。同样使用ST和CT的相互技术，我们将确定哪种细胞一致性负责表型。最后，使用AIM 1中使用的双重应变实验，我们将回答后代“不良”线粒体左上角或新制作的重要问题。在AIM 3中，我们测试了孕产妇干预措施，特别是运动和饮食变化的可能性，可以扭转或挽救这些事件和后代结果。如果成功的话，这些发现将最大程度地增强我们对疾病发展起源的理解，并不仅对繁殖年龄妇女的有效疗法和行为建议的时机，而且对性质有影响。