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)是最常见的肝病，常与肥胖有关 和新陈代谢紊乱。NAFLD的临床病程多种多样，只有部分患者发展为非酒精性 脂肪性肝炎(NASH)和进行性纤维化会增加死亡率。对环境的贡献 NAFLD之前已经通过特殊暴露队列研究和动物模型得到证实。然而， 数据差距阻碍了这一新兴环境健康科学知识的临床应用 通过精准医学途径对NAFLD患者的临床护理。该项目提出了一种新的、高度的-- Impact，虚拟联盟(NAFLD-Victer)，进行协同、多学科、翻译 在成年NAFLD患者中进行暴露组学研究以解决这些知识差距。它检验了这样的假设 环境暴露对非酒精性脂肪肝的严重程度、自然病史和通过肝脏治疗的反应有影响 转录重编程导致代谢紊乱。该财团由调查人员组成 拥有来自三个中心的协同专业知识和资源，包括：Matt Cave(PI，路易斯维尔大学)， Naga Chalasani(印第安纳大学Co-I)和Dean Jones(Co-I，埃默里大学)。具体目标是：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 具有内部比较的分析性横断面研究利用以前收集、归档、确定的 资料来自成年NAFLD患者，其特征是振动控制的瞬时弹性成像和 组织学。无靶向高分辨率曝光组学(HRE)将在血浆中进行。性别差异将是 调查过了。将进行曝光体范围的关联研究(EWAS)与NAFLD严重程度生物标记物的对比。2) 目的：阐明环境暴露增加NAFLD严重程度的机制。这份分析报告 横断面研究利用来自AIM 1的材料以及先前确定的基因分型和肝脏 MRNA-SEQ数据。非靶向高分辨率代谢组学(HRM)将在血浆中进行。Mwas和 将进行转录组广泛关联研究(TWAS)与(I)NAFLD严重程度生物标志物和(Ii) 使用数据驱动的综合和路径分析与NAFLD严重程度相关的暴露。基因： 我们将研究环境之间的相互作用。3)确定与NASH有关的环境化学物质 一项纵向研究中的组织学进展和治疗反应。归档的未识别数据和血浆 样本来自先前发表的成人用乙酰胆酸的多中心安慰剂对照临床试验 纳什将被利用。将进行血浆HRE/HRM检查，并与暴露/代谢特征相关联 NASH患者的组织学进展和对治疗的反应将使用安慰剂和乙酰胆碱来确定 酸处理的患者分别为。NAFLD-Victer将改变临床对环境的理解 对NAFLD的贡献。这将为将暴露组学纳入NAFLD的精准医学铺平道路。