Polychlorinated biphenyls act through EGFR to worsen NAFLD

多氯联苯通过 EGFR 发挥作用，加重 NAFLD

• 批准号: 9328668
• 负责人: Josiah E Hardesty
• 金额: $ 3.05万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9328668
• 关键词: Ablation; Address; Adolescent; Adult; Affect; Affinity; Animal Model; Animals; Binding; Biological Assay; Biological Markers; Calories; Cancer Patient; Chemicals; Competitive Binding; Data; Development; Diabetes Mellitus; Disease; Environmental Exposure; Epidemic; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exposure to; Extracellular Domain; FRAP1 gene; Food Supply; Genetic; Genetic Predisposition to Disease; Goals; Growth; Hepatic; Hepatocyte; High Fat Diet; Human; In Vitro; Intake; Kinetics; Laboratories; Literature; Liver; Liver diseases; Mediating; Metabolic Diseases; Metabolism; Mus; Obesity; Pathway interactions; Phosphorylation; Phosphotransferases; Placenta; Play; Polychlorinated Biphenyls; Population; Predisposition; Prevalence; Production; Proteomics; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recombinant Epidermal Growth Factor; Research; Risk Assessment; Role; STAT3 gene; Serum; Signal Pathway; Signal Transduction; Steatohepatitis; Supplementation; Therapeutic; Time; Toxicology; Woman; Work; c-myc Genes; chemotherapy; chronic liver disease; cohort; constitutive androstane receptor; environmental stressor; in vivo; insight; liver development; liver function; liver injury; loss of function; mortality; non-alcoholic fatty liver; nonalcoholic steatohepatitis; phosphoproteomics; prevent; receptor; receptor binding; receptor function; therapeutic biomarker; therapeutic target; transcription factor

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and diabetes. The development of the NAFLD has previously been assumed to be due to excess calorie intake and genetic predisposition, but our recent studies show that steatosis and steatohepatitis can be exacerbated upon exposure to polychlorinated biphenyls (PCBs). The Anniston, AL cohort, who have higher exposure to PCBs have significant increases in steatohepatitis biomarkers and a prevalence of diabetes relative to healthy populations. Currently there is no well-established mechanism for exacerbated metabolic diseases due to PCB exposure. The literature and our preliminary data characterize PCBs as epidermal growth factor receptor (EGFR) antagonists that diminish activity of downstream effector kinases and transcription factors implicated in NAFLD/Diabetes. The literature and our preliminary data urges us to evaluate PCB-mediated EGFR inhibition as a key feature in the progression of NAFLD/diabetes. As we hypothesize that genetic loss of EGFR function will make mice more susceptible to PCB-mediated NAFLD/diabetes and epidermal growth factor (EGF) supplementation will ablate PCB-driven NAFLD/diabetes. Current risk assessment for PCB- mediated NAFLD/diabetes is limited. We recently characterized PCBs as EGFR antagonists which urges us to evaluate the binding affinities of PCB congeners for the EGFR extracellular domain to develop a EGFR toxic equivalency quotient (TEQ). Our preliminary data suggests that PCBs may outcompete epidermal growth factor (EGF) for EGFR binding at environmental exposure concentrations. We hypothesize that PCB congeners found in human serum directly antagonize the EGFR promoting NAFLD/diabetes. Preliminary data demonstrates that many PCB congeners prevent EGF-mediated phosphorylation of EGFR but only the non-dioxin like (NDL) PCBs are found in human serum at high concentrations. Preliminary proteomic data indicate that while the EGFR pathway is highly affected so are other EGFR independent pathways. To elucidate other hepatic aberrations due to PCB exposure we propose conducting a kinetic phosphoproteomic study in vitro. This will characterize what other pathways are altered due to PCB exposure. The proposed research aims to elucidate signaling pathways altered due to PCB exposure and if those alterations contribute to the development of liver disease and diabetes observed in animals and human populations. I plan to address these questions through genetic loss of function EGFR animal models, therapeutic EGF animal studies, binding assays, and kinetic phosphoproteomic analysis. The proposed research will provide valuable information on altered cell signaling pathways due to PCB mediated NAFLD and elucidate potential therapeutic targets for treatment of organopollutant-induced liver disease.

非酒精性脂肪肝（NAFLD）与肥胖和糖尿病有关。的发展 NAFLD以前被认为是由于过量的卡路里摄入和遗传易感性，但我们的研究表明， 最近的研究表明，脂肪变性和脂肪性肝炎在接触多氯联苯后可能会加剧。 联苯（PCBs）。安尼斯顿，AL队列，谁有较高的暴露于多氯联苯有显着 与健康人群相比，脂肪性肝炎生物标志物和糖尿病患病率增加。 目前，由于多氯联苯暴露而导致的代谢性疾病恶化还没有一个完善的机制。 文献和我们的初步数据表征多氯联苯作为表皮生长因子受体（EGFR） 拮抗剂降低下游效应激酶和转录因子的活性， NAFLD/糖尿病。文献和我们的初步数据促使我们评估PCB介导的EGFR抑制 作为NAFLD/糖尿病进展的关键特征。我们假设EGFR基因缺失 功能将使小鼠更容易受到PCB介导的NAFLD/糖尿病和表皮生长 EGF补充剂将消除PCB驱动的NAFLD/糖尿病。目前对多氯联苯的风险评估- 介导的NAFLD/糖尿病是有限的。我们最近将PCB定性为EGFR拮抗剂，这促使我们 评估PCB同源物对EGFR胞外结构域的结合亲和力，以产生EGFR毒性 当量商（TEQ）。我们的初步数据表明，多氯联苯可能胜过表皮生长 表皮生长因子（EGF）在环境暴露浓度下的EGFR结合。我们假设PCB 在人血清中发现的同源物直接拮抗促进NAFLD/糖尿病的EGFR。初步 数据表明，许多PCB同源物阻止EGF介导的EGFR磷酸化，但只有 在人类血清中发现高浓度的非二恶英类多氯联苯。初步蛋白质组学数据 这表明，虽然EGFR途径受到高度影响，但其他EGFR非依赖性途径也是如此。到 阐明其他肝脏畸变由于PCB暴露，我们建议进行动力学磷酸蛋白质组学 体外研究。这将描述由于PCB暴露而改变的其他途径。拟议 研究旨在阐明由于PCB暴露而改变的信号通路，如果这些改变 有助于在动物和人类中观察到的肝病和糖尿病的发展 人口。我计划通过EGFR基因功能缺失的动物模型来解决这些问题， 治疗性EGF动物研究、结合测定和动力学磷酸蛋白质组学分析。拟议 研究将提供有关PCB介导的NAFLD引起的细胞信号通路改变的有价值的信息， 阐明了治疗有机污染物诱导的肝病的潜在治疗靶点。