Exposome and Precision Medicine in NAFLD

NAFLD 中的暴露组和精准医学

• 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
• 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

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，它往往与肥胖有关 和代谢紊乱NAFLD具有可变的临床病程，并且只有一些患者发展为非酒精性 脂肪性肝炎（NASH）和进行性纤维化，其增加死亡率。对环境的贡献 NAFLD先前已通过特殊暴露队列研究和动物模型得到证实。然而，在这方面， 数据缺口阻碍了这一新兴环境健康科学知识的临床应用， 通过精准医学方法对NAFLD患者进行临床护理。该项目提出了一个新的，高- 影响，虚拟联盟（NAFLD-ViCTER）进行协同，多学科，翻译 在成人NAFLD患者中进行基因组学研究，以解决这些知识差距。它验证了一个假设， 环境暴露有助于NAFLD的严重程度、自然史和对经肝脏途径治疗的反应 转录重编程导致代谢破坏。联合体由调查人员组成 与来自三个中心的协同专业知识和资源，包括：马特洞穴（PI，路易斯维尔大学）， 那牙查拉萨尼（Co-I，印第安纳州大学）和迪安琼斯（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先前收集、存档、去识别的 来自NAFLD成人患者的材料，其特征为振动控制瞬态弹性成像， 组织学将在血浆中进行非靶向高分辨率质谱组学（HRE）。性别差异将是 研究了将进行全暴露体关联研究（EWAS）与NAFLD严重程度生物标志物。（二） 阐明环境暴露增加非酒精性脂肪肝严重程度的机制。该分析 一项横断面研究利用了来自目标1沿着的材料，以及先前确定的基因分型和肝脏 mRNA-SEQ数据。将在血浆中进行非靶向高分辨率代谢组学（HRM）。MWAS和 将进行转录组广泛关联研究（TWAS），对比（i）NAFLD严重程度生物标志物和（ii） 使用数据驱动的综合和途径分析与NAFLD严重程度相关的暴露。吉恩： 将检查环境相互作用。3)确定与NASH相关的环境化学物质 纵向研究中的组织学进展和对治疗的反应。存档的去识别数据和血浆 来自先前发表的奥贝胆酸用于成人的多中心、安慰剂对照临床试验的标本 将使用NASH。将进行血浆HRE/HRM，并将相关暴露/代谢特征 将使用安慰剂和奥贝胆酸确定NASH组织学进展和对治疗的应答。 酸治疗的患者，分别。NAFLD-ViCTER将改变对环境的临床理解 对NAFLD的贡献它将为精准医学在NAFLD中纳入生物学铺平道路。