This is a revised renewal request for year 16-20 of a Program Project Grant (PPG) designed to administratively combine a group of related studies on maternal and fetal cardiovascular signaling at OHSU. This application is submitted in year 15 of ongoing studies. The proposed projects are directed by experienced senior scientists who actively work together. This application is designed to discover underlying mechanisms that regulate the growth and maturation of the cardiomyocyte and its association with the vascular bed of the coronary tree. Our epidemiology work has shown that all of the three main causes of cardiovascular death, which kill more people than any other disease, have their roots in the intrauterine environment. A key feature of the intrauterine environment is its role in determining the number of cardiomyocytes that endure beyond birth and their relationship with vascular elements. Three models of clinically applicable fetal stress will be studied in sheep: fetal anemia, fetal systolic load, placental insufficiency. A low myocyte number is associated with high risk for extensive ischemia reperfusion injury and subsequent heart failure as is excess capillarity. This Program Project includes 3 projects related to cardiomyocyte growth and coronary function and 4 supporting cores. Project I will test the hypothesis that fetal anemic stress leads to pathological changes in the myocardium. Project II tests the hypothesis that systolic load on the fetal myocardium generates an inadequate coronary tree because of limitations of its growth imposed by a reduced cardiomyocyte endowment. Project III tests the hypothesis that growth factors (IGF-1, tri-iodo-L-thyronine and Cortisol) have interacting signaling pathways that mutually operate through the extracellular regulated kinase (ERK) and phosphoinositol-3 kinase pathways and that these pathways can be manipulated to augment the fetal cardiomyocyte endowment. The advantage of the PPG mechanism is the cores that support the projects. Each of the 3 projects will use all cores. Core A is the Administrative Core, Core B is an Animal Core, Core C is the tissue Histopathology Core and Core D in the Ultrasound Imaging Core.
This Program Project Grant is designed to discover 1) the role of fetal low red blood cell count to cause abnormal coronary capillary development, 2) the role of blood pressure load on the developmental function of the fetal coronary tree, 3) the feasibility of using growth factors to augment cell numbers in under grown fetal hearts. These discoveries will make it possible to develop therapies for babies born under conditions described above.
|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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