Role of nuclear receptors in fetal programming

出生体重与产后健康之间的负相关关系是哺乳动物胎儿生物学中最令人着迷的发现之一。控制这种关系的主要假设是遗传和/或表观遗传变化是胎儿发育变化的基础。了解转录因子在介导这些发育事件中的整体作用将使我们更好地了解控制胎儿发育的机制。在本提案中，我们将使用“候选转录因子”方法，首先检查一种脂感核受体家族成员肝X受体（LXR）在大鼠宫内蛋白质限制模型中的作用，该模型参与胆固醇清除，导致出生体重降低，后代生长受损，肝体比降低，胎儿肝脏肥胖增加。通过这一独特的模型，我们首次研究了转录因子和表观遗传标记与靶启动子相互作用的体内发育变化，这些启动子在胎儿发育过程中对基因转录的协调控制起重要作用。

The inverse relationship between birth weight and post partum health is one of the most fascinating discoveries in mammalian fetal biology. The principal hypothesis governing this relationship is that genetic and/or epigenetic changes underlie alterations in fetal development. Understanding the overall role of transcription factors in mediating these developmental events would provide us with a better understanding of the mechanisms controlling fetal development. In this proposal, we will use a 'candidate transcription factor' approach to first examine the role of one lipid-sensing nuclear receptor family member, the Liver X Receptor (LXR), involved in cholesterol clearance, in an intrauterine model of protein restriction in rats, which leads to lower birthweight, impaired offspring growth, decreased liver to body ratio, and an increase in fetal liver adiposity. With this unique model, we can examine for the first time the developmental changes in the in vivo interaction of transcription factors and epigenetic markers to target promoters, which play an important role in the coordinated control of gene transcription during fetal development.