Location: Children's Nutrition Research Center
Project Number: 3092-51000-065-000-D
Project Type: In-House Appropriated
Start Date: Mar 4, 2019
End Date: Mar 3, 2024
Objective:
We will: 1)study the effect of enteral nutrition on the downstream signaling pathways and metabolism;2)study if increased FGF19 availability controls rate of growth, tissue protein synthesis and intestinal development;3)study if being born prematurely blunts protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin; 4)identify by which amino acids, regulate protein synthesis, degradation, and accretion and how responses change with age;5)removed due to investigator departure;6)study molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts;7)study the impact of maternal dietary protein level during lactation;8)study if vitamin D receptors in the brain are critical for glucose regulation;9)study if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A/B reduces gluconeogenesis;10)study the role of the SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway;11)alter DNA methylation in specific subpopulations of hypothalamic neurons and evaluate lifelong effects on energy metabolism, food intake, and PA;12)find the causes of interindividual epigenetic variation and consequences for human energy balance;13)study the functional impact of folic acid supplementation and in intestinal carcinogenesis;14)study the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone and endothelial function; 15)study the effect of vitamin D therapy on change in bone and endothelial function;16)removed due to investigator departure;17)study the CNS circuit architecture and explore circuit complexities that regulate non-homeostatic feeding behaviors via environmental signals transduced by epigenetic mechanisms;18)study the tumorigenic effects of HFCS on a humanized colon tumor mouse model;19)study the effects of HFCS on the gut microbiota of a humanized colon tumor mouse model;20)study the role of HFCS-induced gut microbiota in CRC development; create multi-omic nutritional data share portal to resolve the unmet demand for an efficient access to the large volumes of heterogeneous multi-omic data across various research labs;21)integrate heterogeneous multi-omic datasets such as genetic (SNPs), transcriptomic, epigenetic, proteomic, metabolomic and microbiome to infer molecular network structures illustrating eating disorder dynamics;&22)decode genetic and epigenetic patterns of disordered eating using machine learning methods.
Approach:
This research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will 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. Additionally we will use various rodent models to test leptin's effect on gluconeogenesis that is independent of body weight, and will utilize in vitro experiments employing primary hepatocytes. Scientists will also integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. We will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function. Studies will be conducted in mice that will uncover the molecular basis of interrelationships among dietary sugar, gut microbiota, and CRC development and identify sugar-induced metabolites and/or microbes that can serve as new biomarkers and targets. Researchers will also conduct a multi-omic integrative study to systematically decipher the molecular interplay of disordered eating and neuron specific brain circuits that control feeding behavior.
