Role of nuclear receptors in fetal programming

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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.