Exposome and Precision Medicine in NAFLD

NAFLD 中的暴露组和精准医学

• 批准号: 10064363
• 负责人: Matthew C Cave
• 金额: $ 65.45万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-28 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064363
• 关键词: Acids; Address; Adult; Agonist; Animal Model; Archives; Biological Markers; Clinical; Clinical Research; Cohort Studies; Controlled Clinical Trials; Cross-Sectional Studies; Data; Disease Progression; Doctor of Philosophy; Double-Blind Method; Effectiveness; Environmental Exposure; Environmental Health; Environmental Risk Factor; Etiology; Fibrosis; Funding Mechanisms; Genes; Genetic Transcription; Genotype; Hepatic; Hepatology; Histologic; Histology; Human; Indiana; Institution; Knowledge; Liver; Liver diseases; Longitudinal Studies; Mass Spectrum Analysis; Measurement; Metabolic; National Institute of Environmental Health Sciences; Natural History; Obesity; Participant; Pathogenesis; Pathway Analysis; Patients; Pilot Projects; Placebos; Plasma; Publishing; Research; Research Personnel; Research Subjects; Resolution; Resources; Sampling; Severities; Severity of illness; Sex Differences; Specimen; Steatohepatitis; Strategic Planning; Study models; Testing; Therapeutic; Treatment outcome; Universities; attenuation; authority; clinical application; clinical care; clinical decision-making; cohort; data de-identification; elastography; environmental chemical; gene environment interaction; insight; mRNA sequencing; metabolome; metabolomics; mortality; multidisciplinary; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; precision medicine; prevent; response; transcriptome; vibration; virtual

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, and it is often associated with obesity and metabolic disruption. NAFLD has a variable clinical course, and only some patients develop nonalcoholic steatohepatitis (NASH) and progressive fibrosis which increase mortality. An environmental contribution to NAFLD has previously been demonstrated by special exposure cohort studies and animal models. However, data gaps prevent the clinical application of this emerging environmental health scientific knowledge to impact the clinical care of NAFLD patients through a precision medicine approach. This project proposes a new, high- impact, virtual consortium (the NAFLD-ViCTER) to conduct synergistic, multidisciplinary, translational exposomics research in adult NAFLD patients to address these knowledge gaps. It tests the hypothesis that environmental exposures contribute to NAFLD severity, natural history and response to therapy via hepatic transcriptional reprogramming resulting in metabolic disruption. The consortium is composed of investigators with synergistic expertise and resources from three centers including: Matt Cave (PI, University of Louisville), Naga Chalasani (Co-I, Indiana University), and Dean Jones (Co-I, Emory University). The specific aims are: 1) To determine the environmental exposures associated with adult NAFLD severity in a cross-sectional study. This analytical cross-sectional study with internal comparisons utilizes previously collected, archived, de-identified materials from adult patients with NAFLD characterized by vibration-controlled transient elastography and histology. Untargeted high-resolution exposomics (HRE) will be performed in plasma. Sex differences will be investigated. Exposome-wide association studies (EWAS) vs. NAFLD severity biomarkers will be performed. 2) To elucidate the mechanisms by which environmental exposures increase the severity of NAFLD. This analytical cross-sectional study utilizes materials from Aim 1 along with previously determined genotyping and hepatic mRNA-SEQ data. Untargeted high-resolution metabolomics (HRM) will be performed in plasma. MWAS and transcriptome wide association studies (TWAS) will be performed vs. (i) NAFLD severity biomarkers and (ii) the exposures associated with NAFLD severity using data-driven integrative and pathway analyses. Gene: environment interactions will be examined. 3) To determine the environmental chemicals associated with NASH histologic progression and response to therapy in a longitudinal study. Archived de-identified data and plasma specimens from a previously-published, multi-center, placebo-controlled clinical trial of obeticholic acid for adult NASH will be utilized. Plasma HRE/HRM will be performed and the exposures/metabolic signatures associated with NASH histologic progression and response to therapy will be determined using the placebo and obeticholic acid treated patients, respectively. NAFLD-ViCTER will transform the clinical understanding of the environmental contribution to NAFLD. It will pave the way for precision medicine incorporating exposomics in NAFLD.

非酒精性脂肪性肝病（NAFLD）是最常见的肝脏疾病，通常与肥胖有关