Project III is designed to discover mechanisms that underlie the ability of the immature cardiomyocyte to integrate conflicting hormonal signals that determine the final and optimal cardiomyocyte endowment at birth. Fetal cardiomyocyte endowment is important because it determines the relative force that must be generated by each working cell for the life of offspring and it guides the generation of the coronary architecture within the myocardium. In rats, underendowed hearts are more vulnerable to ischemia-reperfusion injury and heart failure. Based on PPG support we have demonstrated that three hormone/growth factors stimulate cardiomyocyte growth in living near term fetuses: insulin-like growth factor-1 (IGF-1), angiotensin II (Ang II) and Cortisol. Two factors inhibit stimulated cardiomyocyte growth: atrial natriuretic peptide and tri-iodo-L-thyronine (T3). For this project we will study the signaling and actions of IGF-1, T3 and Cortisol. We propose 3 aims that will further our understanding of how these hormones work together and how they might be used to augment cardiomyocte numbers in under-endowed growth restricted hearts.
Aim 1 (in vitro) will test the hypothesis that the hierarchy of signaling action from IGF-1, Cortisol and T3 is based on signal interactions within the mitogen activated protein kinase (MAPK), extracellular regulatory kinase (ERK) and the phosphoinositol 3 kinase (PI3K) pathways in the near term fetal ovine cardiomyocyte.
Aim 2 will test three hypotheses to determine the roles of IGF-1, Taand Cortisol in regulating cardiomyocyte growth and maturation.
The aim speculates that phosphorylation of ERK and PI3-K pathway proteins will be down-regulated in cardiomyocytes in response to subnormal T3 levels which will lead to decreased IGF-1 receptors and increased IGF-1 concentrations.
Aim 3 (in vivo) will test the hypothesis that exogenous IGF-1 and T3 can be used to augment cardiomyocyte numbers permanently in the fetal myocardium. The outcome of the project will be possible therapies for repairing disadvantaged hearts in the womb.
Heart disease has its roots in fetal life, but the mechanisms that regulate the growth and subsequent vulnerability for disease have not been well studied. The completion of these aims will improve our understanding of how heart cell numbers are determined in the fetus and will enlighten or understanding of mechanisms that underlie adult-onset cardiac disease.
|Chattergoon, N N; Louey, S; Stork, P J et al. (2014) Unexpected maturation of PI3K and MAPK-ERK signaling in fetal ovine cardiomyocytes. Am J Physiol Heart Circ Physiol 307:H1216-25|
|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|
|Fan, L; Lindsley, S R; Comstock, S M et al. (2013) Maternal high-fat diet impacts endothelial function in nonhuman primate offspring. Int J Obes (Lond) 37:254-62|
|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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