CDLD Pilot Project 4: The Role for alpha-Lactalbumin-Oliec Acid Complexes in the Diet of Preterm Infants

Katie Chetta – Department of Pediatrics

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The optimal source of nutrition for preterm infants is human milk. Despite the advantages of human milk over formula, and its current high frequency of use, preterm infants continue to suffer from gastrointestinal and digestive issues such as growth and necrotizing enterocolitis (NEC). The long-term goal is to improve the quality of human milk-based diets given to very preterm infants to prevent in-hospital growth failure and NEC. The overall objectives of this application involve (a) to determine the enterocyte response to a milk protein-lipid complex named ‘HAMLET’ (human alpha-lactalbumin made lethal to tumors) and its effects on growth in a neonatal enteroid model in vitro and (b) to evaluate if dietary HAMLET increases the risk of gastrointestinal inflammation using a murine model of NEC. The central hypothesis is that HAMLET will induce apoptosis and cause poor growth in neonatal enteroids and may worsen the severity of NEC and growth failure in animals. The rationale for this project is to determine if HAMLET contributes to these pathologies, and to provide a framework to determine how to study milk containing HAMLET in the diet of preterm infants. The central hypothesis will be tested by 2 specific aims: 1) Identify the type of endocytosis which is involved in absorption of HAMLET into the cell and describe features of the apoptotic pathway 2) Evaluate if HAMLET could increase the risk of severe necrotizing enterocolitis. The first aim will be executed using enteroids developed from neonatal tissues scavenged from clinically-indicated surgeries. Using live 3D imaging, the growth of enteroids will be monitored and apoptosis will be probed using immunohistochemical assays. For the second aim, an established model of necrotizing enterocolitis developed in mice will be used to determine HAMLET􀀊s properties in terms of NEC and growth in vivo. This application is innovative, in the applicant’s opinion, because it focuses on a protein-complex not previously studied in milk diets and neonatal gastrointestinal models. The significance of findings could further justify clinical trials to prevent disease in preterm infants. This knowledge may broaden our perspective regarding novel nutrient complexes and neonatal outcomes.