This is a program project application for funds to study signals across the placenta and within the fetus that regulate the development of the cardiovascular system. The questions that are being posed are fundamental to the underpinnings of cardiovascular disease. Heart and blood vessel diseases are devastatingly high. More people die of this cluster of diseases than from any other cause. In the past decade it has become clear that there are intrauterine causes for heart disease and metabolic syndrome that were once believed to be due to genetic predispositions alone. The adaptive change made in developmental gene expression patterns in response to an early life stressor is called programming. Projects: In this Program Project Grant application we propose 4 projects that address different aspects of the underpinnings of programming. Project 1 tests hypotheses related to the fetal and newborn responses to a high fat diet in maternal monkeys. This project will examine pathological changes in vascular tissue, changes in heart function, alterations in cardiac perfusion and changes in cardiomyocyte growth patterns. Project 2 tests the hypothesis that ovine fetal growth patterns are dictated by hemodynamic loading conditions of the heart. Models of increased and decreased load to the heart will be studied. Project 3 tests the hypothesis that a combination of placental insufficiency and hypertension determines the role of corticosteroid hormones on the growth pattern of immature ovine myocardium. Project 4 test the hypothesis that mitogen activated protein kinase pathways and mammalian target of rapamycin pathways are directly involved in setting the growth patterns of the maturation of the murine myocardium. Significance: Once completed this proposal offers outcomes that will further our knowledge of the mechanisms that program the cardiovascular system. We will be better informed regarding the role of 1) a maternal high fat diet, 2) pressure loading and 3) placental insufficiency and 4) specific signaling pathways in regulating the biological response to stressors during intrauterine life. ? ? ?
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