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）的最大原因，N- 乙酰半胱氨酸（NAC）是唯一可用的药理治疗方法。 NAC仅在早期出现时有效 患者，但大多数患者寻求医疗疗法。因此，有未满足的临床需要 探索针对ALF以后阶段的替代药理方法，例如抑制进展 损伤或增加补偿性肝脏再生。生长因子受体Met和EGFR是 部分肝切除术（pH）被认为是肝脏再生必不可少的，但它们在临床上的作用 APAP诱导的肝损伤（AILI）的相关模型仍未得到充实。与pH值不同，肝损伤和 AILI期间的炎症极大地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与A的再生相同 pH后健康的肝脏。实际上，我们先前发表的研究表明早期EGFR的意外作用 激活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用EGFR治疗相关 抑制剂（Canertinib）几乎完全废除了小鼠的艾利。与EGFR相反，我们的初步研究 表明MET参与了在AILI期间积极抑制肝损伤的进展，除了其作用 促进肝脏再生。因此，我们的总体假设是EGFR并遇到了直径的播放 APAP过量后的急性肝损伤中的作用相反，而不是传统上已知的 在肝细胞增殖中功能相似的作用。与它们在肝脏再生中的相似作用相反， MET直接抑制并自相矛盾的是，EGFR加剧了AILI模型中的急性肝损伤。建立 我们最初的发现提出的范式迁移，我们的具体目的1和2将全面调查 EGFR和MET的作用分别在APAP过量后的肝损伤和补偿性再生中的作用， 利用肝细胞特异性敲除和受体激活策略。此外，我们将调查 这些新型生长因子受体在AILI中的新作用的机制。为了治疗相关性 将研究临床批准的EGFR抑制剂（AFATINIB）和靶向靶向的干预措施的影响 当NAC无效时，AILI，尤其是专注于临床相关的晚期干预措施。最后，对于人类 相关性，我们还将研究干预措施的影响并验证机制 表征了AILI的原代人肝细胞模型。这些研究不仅会阐明再生作用 Met和EGFR，这是在临床上具有重要意义的ALF模型中的第一次，但也将揭示有关该的见解 生长因子受体生物学的新方面与急性肝损伤有关。此外，成功完成 这些研究将有助于确定重新利用临床可用的EGFR抑制剂的潜力 和/或针对靶向的干预措施以治疗APAP诱导的ALF。