Maternal nutrition and oocyte programming

 描述(申请人提供)：肥胖症目前影响美国超过三分之一的育龄妇女，导致整体健康和代谢紊乱，包括生殖功能。肥胖女性的不孕不育率更高，但更重要的是，当她们真的怀孕时，她们的后代会遭受重大的健康后果。肥胖妇女的子女比正常体重妇女所生的子女更有可能在一岁时肥胖，在幼年时患有代谢综合征、高血压和肝脏疾病，并经历发育迟缓、智力残疾和自闭症谱系障碍。鉴于肥胖症流行病的严重性和棘手程度，我们必须确定有效的干预手段，以防止母亲肥胖症的这些有害影响；这需要确定潜在的机制。在这项提案中，我们计划通过卵母细胞编程来确定母亲饮食诱导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周期成分的代谢变化是否以及如何导致有丝分裂失调。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一个步骤在后代中是如何表现的。通过触发、抑制和替换卵母细胞中缺失的部分有丝分裂吞噬，我们希望描述这一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，我们将区分父亲和母亲的mtDNA，并确定父亲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来源是核还是线粒体的问题。利用两位关键合作调查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。同样，使用ST和CT的互换技术，我们将确定哪种细胞成分对表型负责。最后，使用与目标1相同的双品系实验，我们将回答一个重要的问题，即后代“坏”线粒体的起源--是遗留下来的还是新形成的。在目标3中，我们测试了母体干预，特别是锻炼和饮食改变，可以逆转或挽救这些事件和后代结局的可能性。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，并将不仅对育龄妇女提出有效的治疗和行为建议的时机和性质产生影响。

 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.