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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.