PROJECT SUMMARY Applicant. The long-term research goal of the F31 fellowship applicant, William B. Patterson, is to implement advanced statistical modeling approaches to study the biomolecular mechanisms linking environmental exposures and human metabolic diseases. He will be mentored by Drs. Tanya Alderete and Andrea Baccarelli during the training period. Significance. Non-alcoholic fatty liver disease (NAFLD) elevates the risk for cardiometabolic diseases and is increasing in prevalence and severity among adolescents and young adults. Animal and cell-based models suggest that ambient air pollution (AAP) exposure may contribute to NAFLD risk by inducing changes to the expression of circulating microRNAs (miRNAs), a class of non-coding RNAs that regulate gene expression. Circulating miRNA profiles are altered during the onset and progression of NAFLD and in the context of environmental exposures and can serve a “liquid biopsy” that can enable non-invasive insight into exposure and organ-specific pathogenesis. Therefore, circulating miRNAs may represent an important non-invasive mechanistic biomarker of air pollution exposure and NAFLD risk, yet this hypothesis has not yet been studied in humans. Thus, the aim of the current study is to examine associations of AAP exposure with circulating levels of miRNAs and liver fat accumulation among young adults from the Meta-AIR cohort, which is a subset of the Children’s Healthy Study. Aim 1. Determine whether higher AAP exposure is associated hepatic fat fraction and/or NAFLD via whole abdominal MRI scans. Aim 2. 2a) Identify miRNA profiles associated with higher AAP exposure 2b) Determine whether target genes of miRNAs associated with AAP are enriched in metabolic pathways known to play a role in hepatic lipid accumulation. Aim 3. Perform a structural integrated analysis to identify subgroups of young adults that are at risk for NAFLD by testing if AAP exposures and miRNA profiles can predict those with and without NAFLD. Approach. This project will address a shortcoming of previous human exposure studies that have relied on liver enzymes as a proxy for NAFLD by examining hepatic fat fraction from whole abdominal MRI scans and will leverage existing miRNA data from 144 young adults. Aim 3 will employ an innovative tool, LUCID, for integration of exposure and miRNA profiles. During the F31 research and training period, the applicant will acquire significant training in environmental epidemiology and epigenetics research methods. Study results may have important public health implications aimed at reducing AAP exposure and may provide novel insight into clinically relevant clusters of young adults with increased risk for NAFLD given their individual AAP exposure and miRNA profiles. In addition, miRNA inhibitors are increasingly part of therapeutic development and thus important miRNAs identified in this work could provide targets to interrupt the pathways that sustain NAFLD pathophysiology. This proposal i...