Diverging roles of EGFR and MET in acetaminophen-induced acute liver injury

EGFR 和 MET 在对乙酰氨基酚诱导的急性肝损伤中的不同作用

• 批准号: 10633557
• 负责人: Bharat Bhushan
• 金额: $ 41.53万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633557
• 关键词: Acetaminophen; Acetylcysteine; Acute Liver Failure; Address; Analgesics; Antioxidants; Autophagocytosis; Biology; Canertinib; Cell Death Signaling Process; Cessation of life; Clinical; Epidermal Growth Factor Receptor; Functional disorder; Glutathione; Growth Factor Receptors; Hepatocyte; Human; Injury; Intervention; Knock-out; Ligands; Literature; Liver; Liver Failure; Liver Regeneration; MET gene; Mitochondria; Modeling; Mus; Natural regeneration; Oxidation-Reduction; Partial Hepatectomy; Patients; Pharmacological Treatment; Play; Publishing; Receptor Activation; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Recovery; Regenerative response; Role; Severities; Signal Transduction; Source; Therapeutic; Time; Transforming Growth Factor alpha; United States; Work; acetaminophen overdose; acetaminophen-induced liver injury; acute liver injury; clinical effect; clinically relevant; clinically significant; genetic approach; inhibitor; insight; intervention effect; liver cell proliferation; liver inflammation; liver injury; medical attention; novel; novel therapeutics; oxidative damage; pharmacologic; receptor; regenerative

Acetaminophen (APAP) overdose is the topmost cause of acute liver failure (ALF) in the United States, with N- acetylcysteine (NAC) as the only available pharmacological treatment. NAC is effective only in early presenting patients, but majority of these patients seek medical attention late. Thus, there is an unmet clinical need to explore alternative pharmacological approaches targeting later stages of ALF, such as by inhibiting progression of injury or by boosting the compensatory liver regeneration. Growth factor receptors, MET and EGFR, are considered essential for liver regeneration after partial hepatectomy (PH), but their roles in the clinically relevant model of APAP-induced liver injury (AILI) remain underexplored. Unlike PH, massive liver injury and inflammation during AILI greatly govern its pathophysiology and our previous studies have shown that roles of these growth factor receptors in AILI model cannot be presumed identical to that known in regeneration of a healthy liver after PH. In fact, our previously published study indicated an unexpected role of early EGFR activation in aggravating AILI, in contrast to its conventional role in hepatocyte proliferation during regeneration. We found that EGFR activation correlated with the severity of injury and treatment with EGFR inhibitor (canertinib) almost completely abolished AILI in mice. Contrary to EGFR, our preliminary studies indicate that MET is involved in actively suppressing progression of liver injury during AILI, apart from its role in promoting liver regeneration. Thus, our overarching hypothesis is that EGFR and MET play diametrically opposite roles in acute liver injury after APAP overdose, as opposed to their conventionally known and functionally similar roles in hepatocyte proliferation. In contrast to their similar roles in liver regeneration, MET directly suppresses and, paradoxically, EGFR aggravates acute liver injury in the AILI model. To establish the paradigm-shift proposed by our initial findings, our specific aims 1 and 2 will comprehensively investigate the roles of EGFR and MET, respectively, in liver injury and compensatory regeneration after APAP overdose, utilizing hepatocyte-specific knock out and receptor-activation strategies. Further, we will investigate the mechanisms underlying these novel roles of growth factor receptors in AILI. For therapeutic relevance, the effects of clinically-approved EGFR inhibitor (afatinib) and interventions targeting MET will be investigated on AILI, especially focusing on clinically relevant late intervention, when NAC is ineffective. Lastly, for human relevance, we will also investigate the effects of our interventions and validate mechanisms in well- characterized primary human hepatocyte model of AILI. These studies will not only elucidate regenerative role of MET and EGFR, for the first time in a clinically significant ALF model but will also reveal insights into the novel aspect of growth factor receptor biology related to acute liver injury. Moreover, successful completion of these studies will be useful to determine the potential of repurposing a clinically available EGFR inhibitor and/or interventions targeting MET to treat APAP-induced ALF.

对乙酰氨基酚（APAP）过量是美国急性肝衰竭（ALF）的最主要原因，其中N- 乙酰半胱氨酸（NAC）作为唯一可用的药物治疗。NAC仅在早期出现时有效 病人，但大多数病人寻求医疗照顾晚。因此，存在未满足的临床需求， 探索针对ALF晚期的替代药理学方法，例如通过抑制进展 或通过促进代偿性肝再生。生长因子受体，MET和EGFR， 被认为是部分肝切除术（PH）后肝再生的必要条件，但它们在临床上的作用 APAP诱导的肝损伤（AILI）的相关模型仍有待探索。与PH不同，严重的肝损伤和 AILI期间的炎症在很大程度上控制了其病理生理学，我们以前的研究表明， AILI模型中的这些生长因子受体不能被假定为与已知的再生中的相同。 事实上，我们先前发表的研究表明，早期EGFR在PH后的健康肝脏中具有意想不到的作用， 激活加重AILI，与其在肝细胞增殖中的常规作用相反， 再生我们发现EGFR激活与损伤的严重程度和EGFR治疗相关。 抑制剂（canertinib）几乎完全消除小鼠中的AILI。与EGFR相反，我们的初步研究 表明MET除了其作用外，还参与主动抑制AILI期间肝损伤进展 促进肝脏再生因此，我们的总体假设是EGFR和MET在肿瘤的发生发展中起着截然相反的作用。 在APAP过量后急性肝损伤中的相反作用，与其传统上已知的 在肝细胞增殖中的功能相似的作用。与它们在肝再生中的类似作用相反， MET直接抑制AILI模型中的急性肝损伤，并且矛盾的是，EGFR减轻急性肝损伤。建立 我们的初步研究结果提出的范式转变，我们的具体目标1和2将全面调查 EGFR和MET分别在APAP过量后肝损伤和代偿性再生中的作用， 利用肝细胞特异性敲除和受体激活策略。此外，我们将调查 生长因子受体在AILI中的这些新作用的潜在机制。对于治疗相关性， 将研究临床批准的EGFR抑制剂（阿法替尼）和靶向MET的干预措施的作用， AILI，特别是关注NAC无效时的临床相关晚期干预。最后，对于人类 相关性，我们还将调查我们的干预措施的影响，并验证机制，以及- AILI的特征性原代人肝细胞模型。这些研究不仅将阐明再生作用 MET和EGFR，首次在具有临床意义的ALF模型中，但也将揭示对 与急性肝损伤相关的生长因子受体生物学的新方面。此外，圆满完成 这些研究将有助于确定临床上可用的EGFR抑制剂的再利用潜力 和/或靶向MET的干预以治疗APAP诱导的ALF。