Interaction between Genome and Heavy Metals in Nonalcoholic Fatty Liver Disease

非酒精性脂肪肝中基因组与重金属的相互作用

• 批准号: 10658148
• 负责人: Andrea E Cassidy-Bushrow
• 金额: $ 63.1万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658148
• 关键词: Adult; Affect; Age; Alcohol consumption; Alleles; Area; Bioinformatics; Biological Assay; Biopsy; Biopsy Specimen; Cells; Characteristics; Child; Chromatin; Chronic; Clinical; Collaborations; Collection; Communities; Complex; Data; Data Analyses; Deposition; Development; Diabetes Mellitus; Disease; Environment; Environmental Exposure; Environmental Risk Factor; Exposure to; FDA approved; Fibrosis; Fostering; Freezing; Gene Expression; Genes; Genetic Risk; Genome; Genotype; Goals; Health system; Heavy Metals; Hepatocyte; Histologic; Histology; Human; Immune; Individual; Industrialization; Intervention; Knowledge; Liver; Liver Cirrhosis; Malignant neoplasm of liver; Maps; Mediating; Metabolic Diseases; Metabolism; Metal exposure; Metals; Michigan; Modeling; Molecular; Molecular Target; Multiomic Data; Obesity; Pathogenesis; Pathologic; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pharmacotherapy; Population; Predisposition; Preparation; Prevention; Preventive; Quantitative Trait Loci; Research; Risk; Role; Severities; Statistical Models; Testing; Therapeutic; Time; Tissues; Transposase; Validation; Variant; Zinc; aged; cell type; chronic liver disease; cohort; disease diagnosis; disorder prevention; disorder risk; drug discovery; genetic makeup; genetic risk factor; genetic variant; genome wide association study; genome-wide; genome-wide analysis; high risk; insight; liver biopsy; liver transplantation; metropolitan; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel diagnostics; protective effect; response; risk variant; single-cell RNA sequencing; social; stellate cell; tool; transcriptome; transcriptome sequencing; transcriptomics

ABSTRACT The ultimate goal of this project is to discover and validate the gene Х heavy metal (GXM) interactions in human livers and to understand their role in nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common chronic liver disease affecting over 30% of the U.S population, resulting in a heavy social burden. NAFLD is characterized by a spectrum of histological changes with multiple cells involved. Currently, no approved drug treatment is available for NAFLD. Therefore, it is an urgent need to identify both genetic and environmental risk factors to facilitate the development of new diagnostic, preventive, and therapeutic strategies. NAFLD is a typical complex disease involving gene-environment (GXE) interactions. Over the past decade, while GWAS for NAFLD have identified numerous genetic risk alleles, a growing body of research has demonstrated that exposure to heavy metals (Pb, Cd, Hg, As, etc.) are associated with increased NAFLD risk. However, there is no compelling study thus far to assess the correlation between various naturally accumulated metals in human livers and the NAFLD histology, especially in clinically defined patient cohorts. More importantly, there lacks critical knowledge about how naturally and chronically accumulated metals interact with the liver genome and together confer risks for NAFLD. Our preliminary studies in human liver tissues have successfully demonstrated that multiple metals are indeed correlated with NAFLD. By leveraging our previously collected multi-omics data, we have preliminarily identified numerous metal-response genes (MR-genes), expression quantitative traits loci (eQTLs), and allele-specific expression loci (ASEs), which are further enriched to NAFLD and its related pathways. We aim in this study to further expand our study to a large-scale, highly detailed, and integrated analysis to thoroughly understand the role of GXM interactions in NAFLD in humans. To this end, our team has been collaborating to establish collections for human liver tissue, cells and NAFLD patient cohorts. We have also developed various technical platforms e.g. bulk/single cell (Sc) RNAseq and ATAC-seq, as well as multiple bioinformatics and statistical tools for GXE data analyses. With these preparations, we specifically aim: 1) To profile heavy metals in frozen human liver tissues (n=560), identify MR-genes, eQTLs/ASEs, and test their associations with NAFLD; 2) To treat the primary liver cell populations with various metals and to elucidate how the genome of different liver cells respond to metals with Sc-RNAseq and ATAC-seq, and 3) To validate the association between GXM interactions and NAFLD histology severity in a large clinically defined NAFLD patient cohort (n=1313). Our study will for the first time evaluate the role and mechanism of GXM interactions in NAFLD and will provide the scientific community important data to open new avenues to NAFLD research, drug discovery, and beyond.

抽象的 该项目的最终目标是发现和验证基因х重金属（GXM）相互作用 人类的生命并了解其在非酒精性脂肪肝病（NAFLD）中的作用。 NAFLD是最大的 常见的慢性肝病影响了30％以上的美国人口，导致了沉重的社会伯恩。 NAFLD的特征是一系列组织学变化，涉及多个细胞。目前，没有 批准的药物治疗可用于NAFLD。因此，迫切需要确定遗传和 促进新诊断，预防和治疗的环境风险因素 策略。 NAFLD是一种典型的复杂疾病，涉及基因环境（GXE）相互作用。过去 十年，虽然NAFLD的GWAS已经确定了许多遗传风险等位基因，但越来越多的研究已经 证明暴露于重金属（PB，CD，HG，AS等）与NAFLD风险增加有关。 但是，到目前为止，还没有令人信服的研究来评估各种自然之间的相关性 在人类生活和NAFLD组织学中积累的金属，尤其是在临床定义的患者同类中。 更重要的是，缺乏关于自然和长期积累金属的批判性知识 与肝脏基因组互动，并共同为NAFLD互动。我们在人肝的初步研究 组织成功证明了多种金属确实与NAFLD相关。通过利用 我们先前收集的多摩尼克数据，我们已经初步识别了许多金属响应基因 （MR-GENES），表达定量性状基因座（EQTL）和等位基因特异性表达基因座（ASE），它们是 进一步丰富了NAFLD及其相关途径。我们在这项研究中的目标是将研究进一步扩展到 大规模，高度详细和集成的分析，以彻底了解GXM相互作用在 人类中的nafld。为此，我们的团队一直在合作为人类肝组织建立收藏品， 细胞和NAFLD患者队列。我们还开发了各种技术平台，例如散装/单元格（SC） RNASEQ和ATAC-SEQ，以及用于GXE数据分析的多种生物信息学和统计工具。和 这些制剂，我们特别针对：1）在冷冻的人肝组织中介绍重金属（n = 560）， 识别MR-GENES，EQTLS/ASES，并测试其与NAFLD的关联； 2）治疗原发性肝细胞 种群具有各种金属，并阐明不同肝细胞的基因组对金属的反应 SC-RNASEQ和ATAC-SEQ，以及3）验证GXM相互作用与NAFLD之间的关联 在大型临床定义的NAFLD患者队列中的组织学严重程度（n = 1313）。我们的研究将是第一次 评估NAFLD中GXM相互作用的作用和机制，并将提供科学界 重要数据为NAFLD研究，药物发现及其他地区开辟了新的途径。