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.

项目摘要 申请人。F31奖学金申请人William B的长期研究目标。帕特森，是为了实现 先进的统计建模方法来研究生物分子机制， 暴露和人类代谢疾病。他将由Tanya Alderete博士和Andrea Baccarelli博士指导 在训练期间。意义非酒精性脂肪肝（NAFLD）会增加以下风险： 在青少年和年轻人中，心脏代谢疾病的患病率和严重程度正在增加。 基于动物和细胞的模型表明，环境空气污染（AAP）暴露可能导致NAFLD风险 通过诱导循环microRNA（miRNAs）表达的变化， 调节基因表达。循环miRNA谱在NAFLD发作和进展期间发生改变 并且可以用作“液体活组织检查”， 深入了解暴露和器官特异性发病机制。因此，循环中的miRNAs可能代表了 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 还没有在人类身上研究过。因此，本研究的目的是检查AAP暴露的相关性 在Meta-AIR队列的年轻人中， 是儿童健康研究的一部分目标1.确定较高的AAP暴露是否与 肝脏脂肪分数和/或NAFLD。目标2. 2a）鉴定相关的miRNA谱 2b）确定与AAP相关的miRNA的靶基因是否富集在 已知在肝脏脂质蓄积中起作用的代谢途径。目标3.执行结构集成 通过检测AAP暴露和miRNA是否存在， 可以预测那些有和没有NAFLD。Approach.该项目将解决以下缺陷： 先前的人体暴露研究依赖于肝酶作为NAFLD的替代，通过检查肝酶， 脂肪分数从整个腹部MRI扫描，并将利用现有的miRNA数据从144名年轻人。目的 3将采用创新工具LUCID来整合暴露和miRNA谱。在F31研究期间， 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 研究方法研究结果可能具有重要的公共卫生意义，旨在减少AAP暴露 并可能提供新的见解，临床相关集群的年轻人与风险增加NAFLD给予 他们个人的AAP暴露和miRNA谱。此外，miRNA抑制剂越来越多地成为 因此，在这项工作中鉴定的重要miRNAs可以提供靶点，以中断 维持NAFLD病理生理学的途径。该提案与NIEHS战略计划“目标”保持一致 促进环境健康科学”，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。