The major goal of this work is to identify mechanisms whereby changes in maternal diet program postnatal physiology. We will define 1) the manner in which maternal diet influences specific gene products implicated in the mechanisms of programming in the rat placenta during pregnancy; 2) the physiology of the programmed state at the tissue and organ level and 3) the interaction of this state with the immediate postnatal environment Together, these will elucidate the mechanisms, organ specificity and postnatal interactions of an epigenetic programming model. The proposed studies will address the following fundamental questions: 1) Is fetal glucocorticoid exposure the mediator of maternal diet induced programming? 2) Are the end organs of diabetes the target organs of programming? 3) Can the interaction between two epigenetic programming events improve (or worsen) adult physiology? Aim I: Define the mechanisms whereby maternal diet regulates placental 11beta-hydroxysteroid dehydrogenase activity.
Aim II : Define the insulin sensitivity in primary cultures of rat adipocytes and hepatocytes from MLP rats compared to controls Aim III. Define the interaction of maternal diet and postnatal epigenetic regulators on adult blood pressure and insulin sensitivity. The long-term objective of the proposed work is to understand the mechanisms of multi-factorial, epigenetic disease. An understanding of these mechanisms will allow the potential design of therapies in the perinatal period to modify otherwise programmed risk for cardiovascular disease and diabetes, leading causes of death and morbidity in Western society. We expect that a detailed understanding of the mechanisms of programming will allow the design of clinical studies aimed at the improvement of long-term outcome of infants with sub-optimal prenatal growth.
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