Role of Prematurity and Sterol Metabolism in Parenteral Nutrition-Associated Liver Disease

Information

  • Research Project
  • 10445131
  • ApplicationId
    10445131
  • Core Project Number
    K23DK109071
  • Full Project Number
    3K23DK109071-05S1
  • Serial Number
    109071
  • FOA Number
    PA-16-198
  • Sub Project Id
  • Project Start Date
    4/1/2017 - 7 years ago
  • Project End Date
    4/30/2022 - 2 years ago
  • Program Officer Name
    SASLOWSKY, DAVID E
  • Budget Start Date
    1/1/2021 - 3 years ago
  • Budget End Date
    4/30/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    05
  • Suffix
    S1
  • Award Notice Date
    9/3/2021 - 2 years ago

Role of Prematurity and Sterol Metabolism in Parenteral Nutrition-Associated Liver Disease

PROJECT SUMMARY/ABSTRACT 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.

IC Name
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
  • Activity
    K23
  • Administering IC
    DK
  • Application Type
    3
  • Direct Cost Amount
    54900
  • Indirect Cost Amount
    4392
  • Total Cost
    59292
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    847
  • Ed Inst. Type
    SCHOOLS OF MEDICINE
  • Funding ICs
    NIDDK:59292\
  • Funding Mechanism
    OTHER RESEARCH-RELATED
  • Study Section
    DDK
  • Study Section Name
    Kidney, Urologic and Hematologic Diseases D Subcommittee
  • Organization Name
    MEDICAL COLLEGE OF WISCONSIN
  • Organization Department
    PEDIATRICS
  • Organization DUNS
    937639060
  • Organization City
    MILWAUKEE
  • Organization State
    WI
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    532263548
  • Organization District
    UNITED STATES