Lifecourse dietary exposures and offspring hepatic fat in early childhood: a nutrigenomic approach

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PROJECT SUMMARY/ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and carries substantial metabolic and liver-related health risks. Although NAFLD is commonly diagnosed in adolescence, around or after pubertal onset, patients can have varying disease severity at diagnosis, with some having steatohepatitis or advanced fibrosis, suggesting that disease pathogenesis begins much earlier than diagnosis, but is “silent”. From a nutrition perspective, it’s critical that we examine dietary risk factors associated with hepatic fat, especially early on in its development, to better understand the optimal dietary targets and timing for disease prevention. To address this knowledge gap, the proposed research will leverage data/samples from the Healthy Start Study, a longitudinal pre-birth cohort in Colorado that has followed ~1,400 mother-child dyads from pregnancy through early childhood. The specific aims are to: (1) examine independent associations of dietary exposures during distinct lifestages (in utero, infancy, and childhood) with longitudinal hepatic fat from 4-10 yrs; (2) assess the joint and mediating effects of multiple lifecourse dietary exposures on childhood hepatic fat; (3) evaluate whether genetic risk factors for NAFLD modify diet-hepatic fat associations. The central hypothesis is that obesogenic dietary exposures throughout the lifecourse will predict higher hepatic fat deposition in early childhood and that associations will differ in carriers of genetic risk alleles for NAFLD compared to non-carriers. The applicant is a productive PhD scientist and Registered Dietitian, and her long-term career goal is to establish an independent research program that investigates associations of nutritional exposures with pediatric NAFLD risk and severity, and then translates these findings into effective nutrition interventions for preventing NAFLD. To further this goal and to achieve the proposed research aims, the applicant has developed a comprehensive training plan, which will be a logical expansion of her prior background/training and includes the following goals: 1) gain knowledge/skills in lifecourse research and longitudinal analysis; 2) gain knowledge/skills in genomics and nutrigenetics; 3) build expertise in the developmental origins and clinical treatment of pediatric NAFLD; 4) gain experience designing and managing clinical research; 5) enhance research network and professional skills. The University of Colorado Denver-Anschutz Medical Campus is an outstanding research institute with the resources and collaborators needed to facilitate the applicant’s training in these areas. The findings generated from this proposal will generate preliminary data to serve as the foundation for future grant applications, including a career development award, during which the applicant will pursue both observational and clinical-translational research aiming to advance our understanding of the lifecourse determinants and consequences of pediatric NAFLD. Collectively, the proposed research and training will enable the applicant to strategically expand her knowledge, skills, and expertise, and facilitate her transition to independent pediatric nutrition researcher.