Non-alcoholic fatty liver disease (NAFLD) is the most common chronic pediatric liver disease and may progress to an aggressive necro-inflammatory disease (NASH) that leads to fibrosis and cirrhosis in up to 1/3 of affected individuals. The disease mechanisms leading to NAFLD pathogenesis are complex and incompletely understood. Recent evidence indicates a potential link between NASH and obstructive sleep apnea (OSA), both common co-morbidities of obesity. Increased oxidative stress and elevated inflammatory markers occur in both diseases. Mice exposed to intermittent hypoxia, such as occurs in OSA, develop increased hepatic fat deposition. Elevated serum aminotransferases are seen in 20-50% of adults with OSA, and improve with CPAP therapy. Studies to date examining the relationship between NASH and OSA have focused on airflow limitation rather than the more physiologically important hypoxemia. Therefore, we propose the novel hypothesis that chronic intermittent hypoxemia caused by OSA plays a key role in the pathogenesis of NASH through the initiation of oxidative stress and up regulation of inflammatory pathways. To address this, we propose the following Aims: 1) to determine if OSA and nocturnal hypoxemia are associated with increasing severity of liver injury in pediatric NAFLD, 2) to determine if reactive oxygen species generation is associated with hypoxemia and severity of liver injury in pediatric NAFLD and 3) to determine if circulating inflammatory mediators are associated with hypoxemia and severity of liver injury in pediatric NAFLD. This will be investigated in children with biopsy proven NAFLD who will undergo sleep study and control subjects with OSA and/or hypoxemia. Research subjects will undergo testing of blood and urine for evidence of liver injury, metabolic abnormalities, oxidative stress and activation of inflammatory pathways. Changes in the degree of liver injury, oxidant injury and activation of inflammatory pathways will be assessed after correction of OSA/nocturnal hypoxemia. Complimentary to this research program, a five year mentored career development program is proposed that will incorporate both didactic and formal research training guided by two well established investigators with expertise in clinical and translational research in pediatric liver disease, oxidant injury and hypoxemia. The candidate's overarching career goal is to become an independent clinical/translational investigator who will identify novel mechanisms and treatments of NAFLD in children and adolescents. To achieve this goal, the candidate has developed a detailed plan that includes further training in immunology, hypoxemia and oxygen sensing, in vivo human metabolism, genetic and molecular epidemiology and longitudinal data analysis, with ongoing feedback from a formal Career Development Advisory Committee. The proposed research may provide new insights into mechanisms underlying liver injury in pediatric NASH and potentially translate into novel therapeutic and preventive strategies.
(provided by applicant): NAFLD affects ~10% of the general and ~40% of the obese pediatric population. It is unclear what stimulates up to 1/3 of an estimated 1.6 million affected children to develop the more severe NASH. The proposed research will improve the understanding of the mechanistic pathways leading from benign fatty liver to NASH and stimulate new and more efficacious therapeutic strategies for children. NOTE: The criteria scores and the critiques given below were provided by the reviewers assigned to this application. These do not necessarily reflect the positions of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their criteria scores and critiques if their positions changed during the discussion. Please note that the criteria scores are not averaged in arriving at the final overall impact scores. If the reviewers have not changed their criteria scores after the discussion, those shown in the critiques may reflect the opinion of the reviewers before the meeting. The Resume and other initial sections of the summary statement are the authoritative representations of the final outcome of the group discussion. If there is any discrepancy between the reviewers'commentaries and the priority/impact score on the face page of this summary statement, the priority/impact score should be considered the most accurate representation of the final outcome of the group discussion.
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