Exposome and Precision Medicine in NAFLD

NAFLD 中的暴露组和精准医学

基本信息

批准号：
10472017
负责人：
Matthew C Cave
金额：
$ 60.3万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-28 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472017
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 Genotype Hepatic Hepatology Histologic Histology Human Indiana Institution Knowledge 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 Placebo Control 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 liver stiffness mRNA sequencing metabolome metabolomics mortality multidisciplinary non-alcoholic fatty liver disease nonalcoholic steatohepatitis precision medicine prevent transcriptional reprogramming transcriptome treatment response vibration virtual

项目摘要

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.

非酒精性脂肪肝病（NAFLD）是最常见的肝病，通常与肥胖有关和代谢破坏。 NAFLD有一个可变的临床过程，只有一些患者会出现非酒精性脂肪性肝炎（NASH）和进行性纤维化，增加死亡率。环境贡献 NAFLD先前已通过特殊暴露队列研究和动物模型证明。然而，数据差距阻止了这种新兴环境健康科学知识的临床应用来影响通过精确医学方法对NAFLD患者的临床护理。该项目提出了一个新的高级影响，虚拟财团（NAFLD-Victer）进行协同，多学科，翻译成人NAFLD患者的外汇研究研究以解决这些知识差距。它检验了以下假设环境暴露会导致NAFLD的严重程度，自然史和对治疗的反应转录重编程导致代谢中断。该财团由研究人员组成拥有来自三个中心的协同专业知识和资源，包括：马特·凯夫（PI，路易斯维尔大学）， Naga Chalasani（印第安纳大学Co-I）和Dean Jones（Emory University Co-I）。具体目的是：1）在一项横断面研究中，确定与成人NAFLD严重程度相关的环境暴露。这内部比较的分析横截面研究利用了先前收集的，存档，识别的来自NAFLD的成年患者的材料，其特征是振动控制的瞬态弹性摄影和组织学。不靶向的高分辨率释放图（HRE）将在等离子体中进行。性别差异将是调查。将进行全面的社会研究（EWAS）与NAFLD严重性生物标志物。 2）阐明环境暴露会增加NAFLD的严重程度的机制。这个分析横断面研究利用AIM 1的材料以及先前确定的基因分型和肝 mRNA-seq数据。不靶向的高分辨率代谢组学（HRM）将在等离子体中进行。 MWA和转录组范围的研究（TWA）将进行与（i）NAFLD严重性生物标志物和（ii）使用数据驱动的集成和途径分析与NAFLD严重程度相关的暴露。基因：将检查环境互动。 3）确定与纳什相关的环境化学物质在一项纵向研究中，组织学进展和对治疗的反应。存档的去识别数据和等离子体来自先前出版的，多中心的，安慰剂对照的成人临床试验的标本纳什将被利用。将执行血浆HRE/HRM，并与相关的暴露/代谢特征随着NASH的组织学进展和对治疗的反应，将使用安慰剂和obeticholic确定酸治疗的患者分别。 NAFLD-Victer将改变对环境的临床理解对NAFLD的贡献。它将为在NAFLD中纳入杂化学学的精确医学铺平道路。