This proposal, in response to RFA-18-505, is an application for the fourth competitive renewal of the VCU-Emory clinical centers of the NIDDK NASH Clinical Research Network (CRN). It has three specific aims that are aligned with the planned objectives of the renewal of the NASH CRN. Specific aim 1 is to complete recruitment and retain adult and pediatric subjects in the NAFLD Database 3 (DB3) study to support execution, analysis and publication of data to address unmet needs in the field. We will continue enrollment and follow up of participants in the NAFLD Database 3 (DB3) cohort study with collection of bio-samples and clinical data according to the protocol and leverage this data-set to obtain novel insights in to disease biology and validate biomarkers including measurements of spleen stiffness in this population. We already have met our recruitment target and will over-enroll in this study where we have over 90% retention. Specific aim 2 is to fully enroll and complete the ongoing vitamin E dose ranging study of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD). We are close to completing recruitment and expect to meet our enrollment goals by the end of the current funding cycle and have 100% retention in the study. Specific aim 3 is to leverage the transcriptomic dataset generated as part of the NASH CRN ancillary study linked to the CRN database-2 study to validate molecular subclasses of MASLD and their relationship to disease course and outcomes. It builds on our previously published findings that there are distinct transcriptomic profiles within patients with similar histological severity of MASH. Specifically, we will generate novel data on their relationship to histological progression of disease and in those with advanced fibrosis, relate them to time to decompensation and clinical outcomes. A key focus will be to evaluate metabo-inflammation, accelerated aging and fibrogenesis related pathways to disease progression and outcomes. The proposed studies will be highly significant and impact the field as follows: (1) improved understanding of disease evolution including bi- directional interactions in liver and other metabolic dysfunction associated end-organ disease and impact of social and economic determinants of health, (2) acceleration of regulatory qualification of non-invasive tests for clinical use via collaboration with the FNIH NIMBLE project, (3) validation of spleen stiffness measurements and development of other biomarkers, (4) novel insights on disease heterogeneity via the proposed transcriptomic studies and (5) generating foundational data to support future applications for a fully powered trial of vitamin E for metabolic dysfunction associated steatohepatitis (MASH). The VCU and Emory clinical centers have played a robust role in advancing the mission of the NASH CRN and are fully committed to the proposed requirements of the RFA and have the ...