Location: Children's Nutrition Research Center
Project Number: 3092-10700-070-010-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Apr 1, 2019
End Date: Mar 31, 2024
Objective:
Objective 1: Determine the effect of enteral nutrition on FGF19 secretion and the activation of FGF19 receptors and downstream signaling pathways and metabolism in various tissues in neonatal pigs.
Objective 2: Determine whether increased FGF19 availability using parenteral administration of porcine FGF19 and oral FXR agonist treatment controls the rate of growth, tissue protein synthesis and intestinal development in neonatal pigs.
Objective 3: Determine whether being born prematurely blunts the protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin and identify the mechanisms involved.
Objective 4: Identify the mechanisms by which amino acids, particularly leucine and its metabolites, regulate protein synthesis, degradation, and accretion and how these responses change with development.
Objective 5: removed due to investigator departure
Objective 6: Establish the molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts isolated from the offspring of dams fed a low-protein versus an adequate protein diet over critical windows of postnatal development.
Objective 7: Determine the impact of maternal dietary protein level during lactation on biomarkers of one-carbon metabolism in their offspring and establish if the observed effects translate into differences for DNA methylation and/or histone post-translational modifications in satellite cell-derived myoblasts isolated from the skeletal muscles of these offspring.
Approach:
Despite improvements in their nutritional management, most premature and low birth weight infants have experienced growth faltering by discharge. Many remain small to adulthood and are at an increased risk for developing metabolic diseases such as obesity and type 2 diabetes. The goal of this project is to identify the mechanisms that regulate the diminished growth and altered metabolic responses to nutrition in premature and low birth weight infants and to develop new nutritional strategies to optimize their growth and development. Our approach will be to use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. We will determine the role of the enterokine, FGF19, in the anabolic response to enteral feeding in the preterm and whether augmentation of its secretion will enhance growth and metabolic function. We will establish the mechanisms by which undernutrition during critical windows of postnatal development impacts proliferation of skeletal muscle stem cells and the mature muscle nuclear number. Further we will test whether methyl group deficiency induced by inadequate amino acid supply results in permanent epigenetic modifications that impact muscle growth. This project is expected to have a positive impact by providing novel information that will be directly useful in optimizing the nutritional management of premature and low birth weight infants and improving their long-term metabolic health and growth.
