A major hypothesis of this Program Project Grant is that intrauterine stresses can modify the program governing cell growth in adult life by dysregulating proliferative/hypertrophic signals within the heart. Understanding the signaling pathways that couple intrauterine stresses to cardiac growth are directly relevant to the overall goal of this PPG. We propose that selectively manipulating the proliferative and hypertrophic signals within the developing cardiomyocyte will provide an animal model of pathophysiological consequences of altered cardiac cell growth. We will establish genetic models in mice to test this hypothesis. The hypothesis to be tested in this proposal is that modifying hypertrophic and proliferative pathways converge to mediate the growth response in the heart. Studies by Kent Thornburg and co-workers have shown a requirement for extracellular signal-regulated kinase (ERK) and phosphoinositol-3 kinase (PI3-K) in the hyperplastic response of sheep myocardial cells to IGF. Recent studies suggest that PI3-K and ERK signals can also converge on hypertrophic signals via the mTOR pathway that regulates protein translation and growth. Importantly this pathway is also influenced by PI3-K and ERK signaling pathways. One of the major targets of mTOR action, the ribosomal p70 S6 kinase (S6K), is activated by both by PI3-K and ERK signaling pathways. We propose that activation of the mTOR pathway is sufficient for hypertrophy, and that both mTOR and ERKs are necessary for full hypertrophic response to developmental stresses. We predict that constitutive activation of the PI3-K/mTOR cascade is sufficient for cardiac hypertrophy and that both PI3-K/mTOR and ERK pathways are necessary for cardiac hypertrophy. This will be tested in three specific aims using genetically modified animal models of cardiac function.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1)
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Oregon Health and Science University
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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
Midgett, Madeline; Thornburg, Kent; Rugonyi, Sandra (2017) Blood flow patterns underlie developmental heart defects. Am J Physiol Heart Circ Physiol 312:H632-H642
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
Burton, Graham J; Fowden, Abigail L; Thornburg, Kent L (2016) Placental Origins of Chronic Disease. Physiol Rev 96:1509-65
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
Thornburg, Kent L; Kolahi, Kevin; Pierce, Melinda et al. (2016) Biological features of placental programming. Placenta 48 Suppl 1:S47-S53
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
Jonker, S S; Louey, S (2016) Endocrine and other physiologic modulators of perinatal cardiomyocyte endowment. J Endocrinol 228:R1-18

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