This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.There is increasing evidence from epidemiologic and animal studies that a sub-optimal intrauterine environment is a key determinant of the postnatal health of an individual. Our working hypothesis is that a prenatal insult at critical stages of development produces varied effects on placental growth, structure and function through altered gene expression patterns, which modify fetal growth, organ development and the risk of adult disease. The goal of this project is to understand the mechanisms that regulate placental growth and development as well as the factors that 'transmit' risk to the offspring for cardiovascular disease and metabolic disease. Using a non-human primate model of placental insufficiency, we will characterize alterations in placental gene expression profiles (using a candidate gene approach as well as microarray analyses), after the vascular supply to the accessory placental lobe has been ligated at two different gestational ages. We will also document plasma and amniotic fluid biomarkers for putative pathways responsible for compensatory placental growth. We will investigate several families of genes that are most likely affected by placental growth mechanisms, including: i) Growth Regulating Factors (e.g., vascular endothelial growth factor, placental growth factor), ii) Inflammatory Mediators and Pro-oxidants (e.g.,interleukin-6, tumor necrosis factor-alpha and 8-isoprostane), and iii) Nutrient Transporters (e.g., glucose transporters). Molecular and biochemical studies will be complemented by serial ultrasound measurements to correlate fetal hemodynamics and changes in regional circulations (i.e., cerebral, pulmonary and placental blood flow), with fetal body size and proportions through pregnancy in order to understand the hemodynamic influences, which may regulate fetal growth.
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