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. Patterson的长期研究目标是实施 先进的统计建模方法研究了连接环境的生物分子机制 暴露和人类代谢疾病。 Drs将由他打电话。 Tanya Alderete和Andrea Baccarelli 在培训期间。意义。非酒精性脂肪肝病（NAFLD）提高了风险 心脏代谢疾病，青少年和年轻人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（miRNA）的表达变化，这是一类非编码RNA的表达 调节基因表达。在NAFLD的发作和进展过程中，循环miRNA轮廓发生了变化 在环境暴露的背景下，可以进行“液体活检”，可以使无创侵入性 深入了解暴露和器官特异性发病机理。因此，循环miRNA可能代表 重要的非侵入性机械性生物标志物的空气污染暴露和NAFLD风险，但该假设已有 尚未在人类中研究。这是当前研究的目的是检查AAP暴露的关联 来自元空气队列的年轻人中的miRNA和肝脏脂肪的循环水平，这 是儿童健康研究的子集。 AIM 1。确定较高的AAP暴露是否相关 通过整个腹部MRI扫描，肝脂肪分数和/或NAFLD。目标2。2a）识别相关的miRNA轮廓 较高的AAP暴露2b）确定与AAP相关的miRNA的靶基因是否富含 已知在肝脂质积累中发挥作用的代谢途径。目标3。执行结构集成 通过测试AAP暴露和miRNA，分析以识别有NAFLD风险的年轻人的亚组 配置文件可以预测有或没有NAFLD的人。方法。该项目将解决一个缺点 以前的人类暴露研究已通过检查肝酶来依赖肝酶作为NAFLD的代理 整个腹部MRI扫描的脂肪分数，并将利用144名年轻人的现有miRNA数据。目的 3将采用创新工具Lucid来整合暴露和miRNA概况。在F31研究中 和培训期，申请人将接受环境流行病学和表观遗传学的重大培训 研究方法。研究结果可能具有旨在减少AAP暴露的重要公共卫生影响 并可能提供对临床相关的年轻人的新见解，而NAFLD的风险增加 他们的个人AAP暴露和miRNA轮廓。另外，miRNA抑制剂越来越多 治疗性发育，因此在这项工作中确定的重要miRNA可以提供中断的目标 维持NAFLD病理生理学的途径。该建议与NIEHS战略计划“目标”一致 为了推进环境健康科学，特别是强调的大科学和大数据目标 利用创新方法进行大数据集成。