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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD034430-14
Application #
7858234
Study Section
Special Emphasis Panel (ZHD1-MCHG-B (KT))
Program Officer
Ilekis, John V
Project Start
1998-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
14
Fiscal Year
2010
Total Cost
$1,322,189
Indirect Cost
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Midgett, Madeline; Thornburg, Kent; Rugonyi, Sandra (2017) Blood flow patterns underlie developmental heart defects. Am J Physiol Heart Circ Physiol 312:H632-H642
Kolahi, Kevin S; Valent, Amy M; Thornburg, Kent L (2017) Cytotrophoblast, Not Syncytiotrophoblast, Dominates Glycolysis and Oxidative Phosphorylation in Human Term Placenta. Sci Rep 7:42941
Wallace, Alexandra H; Dalziel, Stuart R; Cowan, Brett R et al. (2017) Long-term cardiovascular outcome following fetal anaemia and intrauterine transfusion: a cohort study. Arch Dis Child 102:40-45
Barry, James S; Rozance, Paul J; Brown, Laura D et al. (2016) Increased fetal myocardial sensitivity to insulin-stimulated glucose metabolism during ovine fetal growth restriction. Exp Biol Med (Maywood) 241:839-47
Burton, Graham J; Fowden, Abigail L; Thornburg, Kent L (2016) Placental Origins of Chronic Disease. Physiol Rev 96:1509-65
Chadderdon, Scott M; Belcik, J Todd; Bader, Lindsay et al. (2016) Temporal Changes in Skeletal Muscle Capillary Responses and Endothelial-Derived Vasodilators in Obesity-Related Insulin Resistance. Diabetes 65:2249-57
Kolahi, Kevin; Louey, Samantha; Varlamov, Oleg et al. (2016) Real-Time Tracking of BODIPY-C12 Long-Chain Fatty Acid in Human Term Placenta Reveals Unique Lipid Dynamics in Cytotrophoblast Cells. PLoS One 11:e0153522
Jonker, Sonnet S; Davis, Lowell; Soman, Divya et al. (2016) Functional adaptations of the coronary microcirculation to anaemia in fetal sheep. J Physiol 594:6165-6174
Thornburg, Kent L; Kolahi, Kevin; Pierce, Melinda et al. (2016) Biological features of placental programming. Placenta 48 Suppl 1:S47-S53
Jonker, S S; Louey, S (2016) Endocrine and other physiologic modulators of perinatal cardiomyocyte endowment. J Endocrinol 228:R1-18

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