The goal of this proposal is to provide a pathway to independence as a clinical-translational investigator in the nutrition of premature and critically ill infants. Total parenteral nutrition (TPN) is one of the most common therapies provided in the neonatal intensive care unit (NICU). However, the safety of TPN is significantly limited by the risk for parenteral nutrition-associated liver disease (PNALD). Plant sterols in the soy-based lipid component of TPN are believed to be a contributing factor to liver injury. My prior studies showed that plant sterols are markedly elevated in infants with PNALD and that age impacts sterol metabolism and expression of important hepatic sterol-regulating genes. Two critical gaps in knowledge exist in our understanding of PNALD: 1) the ability of infants to manage exogenous plant sterols during prolonged soy lipid exposure and 2) the mechanism that underlies the vulnerability of neonates to PNALD. My overarching career goal is to close the knowledge gap by becoming an expert in sterol metabolism and PNALD in order to develop and apply novel interventions to improve the safety of TPN in infants. My career development plan logically extends my prior training in neonatology and clinical research. I will attain knowledge and training in translational research, sterol-regulating pathways, iPSC-derived hepatocytes, and liver development. Experienced mentors and a scientific advisory committee at the Medical College of Wisconsin, University of Cincinnati, and the NIH with expertise in multi-center translational research, sterol metabolism, stem cell technologies, and liver development will guide me. I hypothesize that plant sterol concentrations associated with increased risk for PNALD are influenced by gestational age and failure to express key sterol-regulating genes. I will test this hypothesis through two specific aims.
Aim 1 seeks to determine the kinetics of serial plant sterol accumulation and their association with cholestasis in infants receiving prolonged soy lipids. This will be done using a prospective, multicenter clinical study to measure serial plant sterol and cholesterol levels in the blood of infants during soy lipid therapy of at least 2 weeks.
Aim 2 seeks to identify gene expression and lipid accumulation in patient-derived hepatocytes exposed to plant sterols at different developmental stages. This will be assessed using immature and mature hepatocytes derived from the iPSC of matched study participants with and without PNALD. Results and expertise acquired during this award will position me to establish an independent, clinical-translational research program to ultimately improve the safety of nutrition in critically ill neonates.
Parenteral nutrition-associated liver disease (PNALD) has a significant negative impact on the safety of total parenteral nutrition (TPN) in critically ill infants. There is a lack of understanding of why infants, particularly premature infants, are the most susceptible group for severe liver injury and death from PNALD. The proposed research will study the underlying reason why infants develop PNALD by focusing on the ability of infants to get rid of potentially liver-damaging plant sterols contained in TPN and how developmental maturity affects pathways for their elimination.
|McAndrew, Sarah; Acharya, Krishna; Nghiem-Rao, T Hang et al. (2018) NICU management and outcomes of infants with trisomy 21 without major anomalies. J Perinatol 38:1068-1073|
|Khalil, Syed Tariq; Uhing, Michael R; Duesing, Lori et al. (2017) Outcomes of Infants With Home Tube Feeding: Comparing Nasogastric vs Gastrostomy Tubes. JPEN J Parenter Enteral Nutr 41:1380-1385|
|Acharya, K; Leuthner, S; Clark, R et al. (2017) Major anomalies and birth-weight influence NICU interventions and mortality in infants with trisomy 13 or 18. J Perinatol 37:420-426|