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.

项目摘要在国家职业研究所确定的近700个工作场所化学物质中，约有33％安全与健康（NIOSH）口袋指南与肝毒性有关。其中几个已链接增加不同占领环境中工人的肝病死亡率，例如重型结构设备操作员，烟囱清扫机和化学工人。异生物诱导的肝毒性是以氧化应激，注射和纤维化为特征，在以后的阶段，可能导致肝衰竭和肝细胞癌（HCC）。虽然炎症已暗示转录扰动和纤维化；转录后调节在异生元诱导的肝发育中的作用炎症和纤维化尚不清楚。 RNA结合蛋白（RBPS）的三烷基二烷（TTP）家族包括锌指蛋白36（ZFP36）通常称为TTP，锌指蛋白36如1（ZFP36L1），和锌指蛋白36如2（ZFP36L2），是转录后调节的主要参与者与炎症相关的mRNA数量。这些蛋白质与3'untranslated上的Au富元素（ARE）结合目标mRNA的区域（3'UTRS）并促进其衰变。 TTP家族RBP在人HCC中失调。工业化学物质，包括氯吡啶磷，四氯二苯二氮蛋白（TCDD）和四氯化碳（CCL4），也使TTP家族RBP的表达不足。但是，下游分子和细胞效应在宿主上的这些失调中，仍未知。在此提案中，我们将检验我们的新假设 TTP家族RBPS表达的异源生物诱导的失调导致转录后调节改变这决定了肝脏注射和纤维化的发病机理。我们将使用CCL4引起的肝脏炎症和纤维化是肝毒性的模型，并通过三个特定目标检验我们的假设。 AIM 1，我们将在小鼠中采用三个RBP的肝特异性消融，并采用新颖的“ OMIC”方法来测试这些RBP调节异种生物诱导的肝脏注射和纤维化的致病机制。目的 2将表征TTP家族RBP调节上皮的细胞和分子机制间充质转变，纤维化和肿瘤转移的主要原因，最后，AIM 3将测试是否是否增加TTP家族RBP在肝脏中的表达可预防异生物生物诱导的肝炎症和纤维化。拟议研究的总体目标是了解TTP家族RBP的作用介导的转录后调节在异生物生物诱导的肝毒性的发病机理中。成功的拟议研究的完成将对对机械的理解产生重大影响异种生物诱导的肝病的病理生理学以及TTP家族RBP的潜在鉴定为内源性抗炎/抗纤维化蛋白的活性可能会增强以延迟或防止肝衰竭的发作。