Modulation of RNA Binding Proteins in Xenobiotic-induced Hepatotoxicity

RNA 结合蛋白在异生素诱导的肝毒性中的调节

基本信息

批准号：
10587498
负责人：
Yogesh Saini
金额：
$ 46.44万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-09 至 2023-09-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10587498
关键词：
3&apos Untranslated Regions Ablation Adverse effects Anti-Inflammatory Agents Binding Proteins Biochemical Bioinformatics Biological Markers Carbon Tetrachloride Cell Nucleus Chemicals Chlorpyrifos Cholestasis Data Development Dioxins Disease Disease model Down-Regulation Elements Environmental and Occupational Exposure Epithelium Equipment Exposure to Family Fibrosis Functional disorder Future Gene Expression Regulation Genetic Genetic Transcription Goals Hepatocyte Hepatotoxicity Homeostasis Human In Vitro Industrialization Inflammation Inflammatory Knockout Mice Knowledge Lead Link Liver Liver Failure Liver Fibrosis Liver diseases Malignant Epithelial Cell Mediating Mesenchymal Messenger RNA Methods Modeling Molecular Mus National Institute for Occupational Safety and Health Neoplasm Metastasis Occupational Oncogenic Oxidative Stress Oxidative Stress Induction Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Play Post-Transcriptional Regulation Primary carcinoma of the liver cells Prognostic Marker Proteins RNA-Binding Proteins Recombinants Research Role Stains TIS11 protein Testing The Cancer Genome Atlas Therapeutic Therapeutic Intervention Tissues Viral Workplace Xenobiotics ZFP36L2 gene Zinc Fingers Zinc deficiency biomarker identification carcinogenesis cellular targeting diagnostic biomarker dibenzo(1,4)dioxin early detection biomarkers epithelial to mesenchymal transition feasibility testing fibrogenesis gain of function in vivo innovation liver inflammation liver injury mortality mouse model novel overexpression posttranscriptional prevent prognostic indicator prognostic value protective effect protein expression response therapeutic development transcriptome transcriptome sequencing tumor tumorigenic

项目摘要

Project Summary Approximately 33% of the nearly 700 workplace chemicals identified in the National Institute of Occupational Safety and Health (NIOSH) Pocket Guide are associated with hepatotoxicity. Several of these have been linked to increased liver disease mortality in workers in different occupational settings such as heavy construction equipment operators, chimney sweepers, and chemical workers. Xenobiotic-induced hepatotoxicity is characterized by oxidative stress, inflammation, and fibrosis, which, in later stages, may result in hepatic failure and hepatocellular carcinoma (HCC). While transcriptional perturbations have been implicated in inflammation and fibrosis; the role of post-transcriptional regulation in the development of xenobiotic-induced hepatic inflammation and fibrosis is unclear. The tristetraprolin (TTP) family of RNA binding proteins (RBPs) including zinc finger protein 36 (ZFP36) commonly referred to as TTP, zinc finger protein 36 like 1 (ZFP36L1), and zinc finger protein 36 like 2 (ZFP36L2), are the key players in post-transcriptional regulation of a large number of inflammation-relevant mRNAs. These proteins bind to AU-rich elements (AREs) on the 3’untranslated regions (3’UTRs) of target mRNAs and promote their decay. TTP family RBPs are dysregulated in human HCC. Industrial chemicals including chlorpyrifos, tetrachlorodibenzo-p-dioxin (TCDD), and carbon tetrachloride (CCl4), also dysregulate the expression of TTP family RBPs. However, the downstream molecular and cellular effects of these dysregulations on the host remain unknown. In this proposal, we will test our novel hypothesis that xenobiotic-induced dysregulation of TTP family RBPs expression results in altered post-transcriptional regulation that determines the pathogenesis of hepatic inflammation and fibrosis. We will use CCl4-induced liver inflammation and fibrosis as a model of hepatotoxicity and test our hypothesis through three specific aims. In Aim 1, we will employ liver-specific ablations of the three RBPs in mice and novel “omics” approaches to test the pathogenic mechanisms by which these RBPs regulate xenobiotic-induced liver inflammation and fibrosis. Aim 2 will characterize the cellular and molecular mechanisms by which TTP family RBPs regulate epithelial- mesenchymal transition, a lead cause of fibrosis and tumor metastasis, and finally, Aim 3 will test whether increasing the expression of TTP family RBPs in the liver protects against xenobiotic-induced hepatic inflammation and fibrosis. The overall goal of the proposed research is to understand the role of TTP family RBP mediated post-transcriptional regulation in the pathogenesis of xenobiotic-induced hepatotoxicity. Successful completion of the proposed studies will have a significant impact on the mechanistic understanding of the pathophysiology of xenobiotic-induced liver disease and the potential identification of TTP family RBPs as endogenous anti-inflammatory/anti-fibrotic proteins whose activity could be possibly enhanced to delay or prevent the onset of liver failure.

项目概要美国国家职业研究所确定的近 700 种工作场所化学品中约有 33% 安全与健康 (NIOSH) 袖珍指南与肝毒性有关。不同职业环境（例如重型建筑）工人的肝病死亡率增加设备操作员、烟囱清扫工和化学工人。以氧化应激、炎症和纤维化为特征，在后期可能导致肝衰竭和肝细胞（HCC），而转录癌扰动与炎症有关。和纤维化；转录后调控在异生素诱导的肝发育中的作用三四脯氨酸 (TTP) 家族的 RNA 结合蛋白 (RBP) 与炎症和纤维化的关系尚不清楚。包括通常称为TTP的锌指蛋白36（ZFP36）、锌指蛋白36样1（ZFP36L1）、和锌指蛋白 36 like 2 (ZFP36L2)，是一个大转录后调节的关键角色。这些蛋白质与 3’非翻译区富含 AU 的元件 (ARE) 结合。靶 mRNA 的区域（3’UTR）并促进其衰变，在人类 HCC 中失调。工业化学品包括毒死蜱、四氯二苯并二恶英 (TCDD) 和四氯化碳 (CCl4)，也调节 TTP 家族 RBP 的表达，但下游分子和细胞效应。宿主身上的这些失调仍然未知。在这个提案中，我们将测试我们的新假设：异生素诱导的 TTP 家族 RBP 表达失调导致转录后调节改变这决定了肝脏炎症和纤维化的发病机制，我们将使用CCl4诱导的肝脏。炎症和纤维化作为肝毒性模型，并通过三个具体目标检验我们的假设。目标 1，我们将采用小鼠肝脏特异性消融三种 RBP 和新颖的“组学”方法来测试这些 RBP 调节异生素诱导的肝脏炎症和纤维化的致病机制。图 2 将描述 TTP 家族 RBP 调节上皮细胞的细胞和分子机制。间质转化是纤维化和肿瘤转移的主要原因，最后，目标 3 将测试是否增加肝脏中 TTP 家族 RBP 的表达可预防外源性肝病本研究的总体目标是了解 TTP 家族 RBP 的作用。介导的外源性肝毒性发病机制中的转录后调控已成功。完成拟议的研究将对机制的理解产生重大影响外源性肝病的病理生理学以及 TTP 家族 RBP 的潜在鉴定内源性抗炎/抗纤维化蛋白，其活性可能被增强以延迟或预防肝衰竭的发生。