Sunday, April 28, 2024
4/28/2024
PROJECT SUMMARY Preterm birth is the leading cause of infant mortality in the United States and is associated with long-term dysfunctions in growth. This is, in part, a result of immature gastrointestinal function and reduced digestive and metabolic responses to feeding, making it difficult to assimilate enteral nutrition for growth. However, mechanisms underpinning the blunted response to enteral nutrition and growth dysfunction in preterm neonates are poorly understood. Fibroblast Growth Factor-19 (FGF19) is a potent fetal growth factor, but postnatally, FGF19 is secreted by the distal ileum in response to bile acid stimulation and negatively regulates hepatic bile acid synthesis. Preterm infants have a bile acid pool that is one-third the size of term infants and this smaller bile acid pool may limit fat digestion and FGF19 secretion. Our recent studies in neonatal pigs showed that the plasma FGF19 is markedly lower in preterm vs. term, and the lower FGF19 is driven by lower ileal responsiveness to bile acid stimulation and a smaller hepatic bile acid pool. Pigs born vaginally had plasma FGF19 levels 35 times greater than term pigs born via cesarean section and 70 times higher than preterm pigs at birth. Among these groups of pigs, plasma cortisol directly correlated with plasma FGF19 concentrations. This latter finding may be important since preterm infants are often given glucocorticoids perinatally to improve respiratory function. In the proposed studies, I hypothesize that glucocorticoids upregulate the developmental responses to bile acid homeostasis and FGF19 signaling in the perinatal period. In Aim 1A we will characterize the developmental differences in molecular and cellular signaling pathways in preterm and term hepatocytes and intestinal enteriods and examine their association with cortisol, bile acid homeostasis and FGF19 signaling. In Aim 1B we will determine the effect of birth modality (vaginal versus cesarean section) and glucocorticoid treatment (maternal and neonatal) on gut-liver bile acid homeostasis and FXR-FGF19 signaling in neonatal pigs. In Aim 2, we will directly assess the effect of an enteral FXR agonist and hydrocortisone on the rate of growth, tissue protein synthesis and intestinal development in preterm neonatal pigs. The results of these aims will establish the role of perinatal glucocorticoids on bile acid homeostasis and FGF19 signaling and whether FGF19 functions to improve neonatal growth. My long-term career goal is to establish an independent, academic research program to interrogate the effects of preterm birth on perinatal hepatic and gastrointestinal development and physiology. I have assembled an expert mentorship committee to guide my development as an independent investigator. My mentor, Dr. Doug Burrin has a record of accomplishment using neonatal pigs to model human infant nutrition and development. Completion of these aims will allow me to pursue additional training and develop skills in molecular techniques, cell culture, advanced imaging, and bioinformatics.
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