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: 10647694
• 负责人: William Brooks Patterson
• 金额: $ 4.03万
• 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/10647694
• 关键词: Abdomen; Adolescent and Young Adult; Affect; Air Pollutants; Air Pollution; American; Animal Model; Animals; Atherosclerosis; Big Data; Biological Markers; CD36 gene; Cardiac; Cardiometabolic Disease; Cells; Child; Child Health; Cirrhosis; 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; Pathogenesis; Pathologic; Pathway interactions; Prevalence; Proxy; Public Health; Research; Research Methodology; 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; 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.

项目概要 F31 奖学金申请人 William B. Patterson 的长期研究目标是实施。 先进的统计建模方法来研究与环境相关的生物分子机制 他将接受 Tanya Alderete 和 Andrea Baccarelli 博士的指导。 训练期间非酒精性脂肪肝（NAFLD）的风险增加。 心脏代谢疾病在青少年和年轻人中的患病率和严重程度正在增加。 动物和细胞模型表明，环境空气污染 (AAP) 暴露可能会增加 NAFLD 风险 通过诱导循环 microRNA (miRNA) 表达的变化，miRNA 是一类非编码 RNA， 调节基因表达在 NAFLD 的发病和进展过程中发生改变。 在环境暴露的情况下，可以进行“液体活检”，从而实现非侵入性 因此，循环 miRNA 可能代表了暴露和器官特异性发病机制。 空气污染暴露和 NAFLD 风险的重要非侵入性机械生物标志物，但这一假设 尚未在人类中进行研究，因此，当前研究的目的是检查 AAP 暴露的关联。 Meta-AIR 队列中年轻人的 miRNA 循环水平和肝脏脂肪积累， 是儿童健康研究的一个子集。目标 1。确定较高的 AAP 暴露是否与之相关。 通过全腹部 MRI 扫描了解肝脏脂肪分数和/或 NAFLD 目标 2. 2a) 识别相关 miRNA 谱。 具有较高的 AAP 暴露 2b) 确定与 AAP 相关的 miRNA 的靶基因是否富集 已知在肝脏脂质积累中发挥作用的代谢途径 目标 3. 进行结构整合。 通过测试 AAP 暴露和 miRNA 是否存在分析来识别有 NAFLD 风险的年轻人亚组 该项目将解决NAFLD 的一个缺点。 之前的人类暴露研究通过检查肝脏，依赖肝酶作为 NAFLD 的替代指标 来自整个腹部 MRI 扫描的脂肪分数，并将利用来自 144 名年轻人的现有 miRNA 数据。 3 将在 F31 研究期间采用创新工具 LUCID 来整合暴露和 miRNA 谱。 和培训期间，申请人将获得环境流行病学和表观遗传学方面的重要培训 研究方法可能对减少 AAP 暴露具有重要的公共卫生影响。 并可能为临床相关的 NAFLD 风险增加的年轻人群提供新的见解 他们各自的AAP暴露和miRNA谱此外，miRNA抑制剂也越来越成为其中的一部分。 治疗的发展以及这项工作中发现的重要 miRNA 可以提供中断治疗的靶标。 该提案与 NIEHS 战略计划“目标”一致。 促进环境健康科学”，特别是强调大科学和大数据的目标 创新利用大数据集成方法。