Exposure to Ambient Air Pollutants, Circulating microRNAs, and Hepatic Fat Fraction Among Young Adults

年轻人接触环境空气污染物、循环 microRNA 和肝脂肪分数

• 批准号: 10537895
• 负责人: William Brooks Patterson
• 金额: $ 3.93万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-14 至 2025-06-13
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537895
• 关键词: Abdomen; Address; Adolescent and Young Adult; Affect; Air Pollutants; Air Pollution; Alcoholic Liver Cirrhosis; American; Animal Model; Animals; Atherosclerosis; Big Data; Biological Markers; Cardiac; Cardiometabolic Disease; Cells; Child; Child Health; Communication; Cross-Sectional Studies; Data; Diagnostic; Disease; Environmental Epidemiology; Environmental Exposure; Environmental Health; Enzymes; Epigenetic Process; Exposure to; Extrahepatic; FASN gene; Fatty Acids; Fatty acid glycerol esters; Fellowship; Functional disorder; Gene Expression; Genes; Goals; Health; HepG2; Hepatic; Hepatocyte; Human; Individual; Interruption; Knowledge; Link; Lipids; Lipolysis; Literature; Liver; MRI Scans; Magnetic Resonance Imaging; Mentors; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic Pathway; MicroRNAs; Modeling; National Institute of Environmental Health Sciences; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Organ; Ozone; PPAR alpha; Particulate Matter; Pathogenesis; Pathologic; Pathway interactions; Play; Prevalence; Proxy; Public Health; Research; Research Methodology; Research Training; Risk; Risk Factors; Role; Science; Scientific Advances and Accomplishments; Serum; Severities; Statistical Models; Strategic Planning; Structure; Subgroup; System; Technology; Testing; Tissues; Training; Transcript; Transforming Growth Factor beta; Treatment Efficacy; Triglycerides; United States; Untranslated RNA; Work; ambient air pollution; base; cardiometabolic risk; circulating microRNA; clinically relevant; cohort; comorbidity; data integration; diabetes risk; diagnostic biomarker; disorder risk; early detection biomarkers; early onset; exposed human population; fatty acid biosynthesis; fatty acid oxidation; fine particles; inhibitor; innovation; insight; lipid metabolism; liquid biopsy; liver injury; nano-string; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; noninvasive diagnosis; novel; ozone exposure; public health intervention; therapeutic development; tool; translocase; uptake; young adult

PROJECT SUMMARY Applicant. The long-term research goal of the F31 fellowship applicant, William B. Patterson, is to implement advanced statistical modeling approaches to study the biomolecular mechanisms linking environmental exposures and human metabolic diseases. He will be mentored by Drs. Tanya Alderete and Andrea Baccarelli during the training period. Significance. Non-alcoholic fatty liver disease (NAFLD) elevates the risk for cardiometabolic diseases and is increasing in prevalence and severity among adolescents and young adults. Animal and cell-based models suggest that ambient air pollution (AAP) exposure may contribute to NAFLD risk by inducing changes to the expression of circulating microRNAs (miRNAs), a class of non-coding RNAs that regulate gene expression. Circulating miRNA profiles are altered during the onset and progression of NAFLD and in the context of environmental exposures and can serve a “liquid biopsy” that can enable non-invasive insight into exposure and organ-specific pathogenesis. Therefore, circulating miRNAs may represent an important non-invasive mechanistic biomarker of air pollution exposure and NAFLD risk, yet this hypothesis has not yet been studied in humans. Thus, the aim of the current study is to examine associations of AAP exposure with circulating levels of miRNAs and liver fat accumulation among young adults from the Meta-AIR cohort, which is a subset of the Children’s Healthy Study. Aim 1. Determine whether higher AAP exposure is associated hepatic fat fraction and/or NAFLD via whole abdominal MRI scans. Aim 2. 2a) Identify miRNA profiles associated with higher AAP exposure 2b) Determine whether target genes of miRNAs associated with AAP are enriched in metabolic pathways known to play a role in hepatic lipid accumulation. Aim 3. Perform a structural integrated analysis to identify subgroups of young adults that are at risk for NAFLD by testing if AAP exposures and miRNA profiles can predict those with and without NAFLD. Approach. This project will address a shortcoming of previous human exposure studies that have relied on liver enzymes as a proxy for NAFLD by examining hepatic fat fraction from whole abdominal MRI scans and will leverage existing miRNA data from 144 young adults. Aim 3 will employ an innovative tool, LUCID, for integration of exposure and miRNA profiles. During the F31 research and training period, the applicant will acquire significant training in environmental epidemiology and epigenetics research methods. Study results may have important public health implications aimed at reducing AAP exposure and may provide novel insight into clinically relevant clusters of young adults with increased risk for NAFLD given their individual AAP exposure and miRNA profiles. In addition, miRNA inhibitors are increasingly part of therapeutic development and thus important miRNAs identified in this work could provide targets to interrupt the pathways that sustain NAFLD pathophysiology. This proposal is aligned with the NIEHS Strategic Plan “Goals for Advancing Environmental Health Sciences”, particularly the Big Science and Big Data goal which emphasizes utilization of innovative approaches for big data integration.

项目总结 申请人。F31奖学金申请人威廉·B·帕特森的长期研究目标是实施 先进的统计建模方法用于研究与环境相关的生物分子机制 暴露与人类代谢性疾病。他将由Tanya Alderete博士和Andrea Baccarelli博士指导 在训练期间。意义重大。非酒精性脂肪性肝病(NAFLD)会增加罹患 心脏代谢性疾病，在青少年和青壮年中的患病率和严重性正在增加。 基于动物和细胞的模型表明，环境空气污染(AAP)暴露可能会增加NAFLD的风险 通过诱导循环中的microRNAs(MiRNAs)表达的变化，一类非编码RNAs 调控基因表达。在NAFLD的发生和发展过程中循环miRNA图谱发生变化 在环境暴露的情况下，并可以提供能够实现非侵入性 对暴露和器官特有的致病机制的洞察。因此，循环中的miRNA可能代表一种 空气污染暴露和NAFLD风险的重要非侵入性机械生物标志物，然而这一假说 还没有在人类身上进行研究。因此，当前研究的目的是检查AAP暴露的相关性 来自Meta-Air队列的年轻人循环中的miRNAs水平和肝脏脂肪积累，这是 是儿童健康研究的一个子集。目标1.确定较高的AAP暴露是否与 肝脏脂肪分数和/或非酒精性脂肪性肝病通过全腹部MRI扫描。目标2.2a)确定相关的miRNA图谱 与较高的AAP暴露2b)确定与AAP相关的miRNAs的目标基因是否在 已知的代谢途径在肝脏脂肪堆积中起作用。目标3.执行结构集成 通过检测AAP暴露和miRNA来识别有患NAFLD风险的年轻人亚群的分析 个人资料可以预测有或没有NAFLD的人。接近。该项目将解决以下缺点 以前的人类暴露研究依赖肝酶作为NAFLD的代用品，通过检查肝脏 来自全腹部MRI扫描的脂肪部分将利用来自144名年轻人的现有miRNA数据。目标 3将采用一种创新的工具，Lucid，用于整合暴露和miRNA配置文件。在F31研究期间 和培训期间，申请者将获得环境流行病学和表观遗传学方面的重要培训 研究方法。研究结果可能对减少AAP接触具有重要的公共卫生影响 并可能为临床相关的年轻人群体提供新的见解，这些年轻人的NAFLD风险增加 他们各自的AAP暴露和miRNA图谱。此外，miRNA抑制剂越来越多地成为 这项工作中确定的治疗开发和因此重要的miRNAs可以提供靶点来中断 支持NAFLD病理生理学的途径。该提案与NIEHS战略计划的目标相一致 为了推进环境健康科学“，特别是大科学和大数据目标，强调 利用创新方法进行大数据整合。