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.
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|Rinkevich, Diana; Belcik, Todd; Gupta, Nandita C et al. (2013) Coronary autoregulation is abnormal in syndrome X: insights using myocardial contrast echocardiography. J Am Soc Echocardiogr 26:290-6|
|Thornburg, Kent L; Louey, Samantha (2013) Uteroplacental circulation and fetal vascular function and development. Curr Vasc Pharmacol 11:748-57|
|Anderson, Debra F; Jonker, Sonnet S; Louey, Samantha et al. (2013) Regulation of intramembranous absorption and amniotic fluid volume by constituents in fetal sheep urine. Am J Physiol Regul Integr Comp Physiol 305:R506-11|
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|Chattergoon, Natasha N; Giraud, George D; Louey, Samantha et al. (2012) Thyroid hormone drives fetal cardiomyocyte maturation. FASEB J 26:397-408|
|Bernard, Leah S; Hashima, Jason N; Hohimer, A Roger et al. (2012) Myocardial performance and its acute response to angiotensin II infusion in fetal sheep adapted to chronic anemia. Reprod Sci 19:173-80|
|Back, Stephen A; Riddle, Art; Dean, Justin et al. (2012) The instrumented fetal sheep as a model of cerebral white matter injury in the premature infant. Neurotherapeutics 9:359-70|
|Chattergoon, Natasha N; Louey, Samantha; Stork, Philip et al. (2012) Mid-gestation ovine cardiomyocytes are vulnerable to mitotic suppression by thyroid hormone. Reprod Sci 19:642-9|
|Thornburg, Kent; Jonker, Sonnet; O'Tierney, Perrie et al. (2011) Regulation of the cardiomyocyte population in the developing heart. Prog Biophys Mol Biol 106:289-99|
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