Mechanisms of Liver Regeneration After Acetaminophen-Induced Acute Liver Failure

描述（由申请人提供）：对乙酰氨基酚（APAP）是一种常用的镇痛和解热药物，过量使用是发展中国家急性肝衰竭（ALF）的最常见原因。apap诱导的ALF的治疗选择非常有限。大多数ALF患者接受n -乙酰半胱氨酸治疗，这是一种谷胱甘肽的前体，只有在APAP过量后数小时内给予治疗才有效。唯一的其他治疗方法是肝移植，但由于供体器官稀缺、终身使用免疫抑制剂和高昂的费用，这一治疗方法变得复杂。迫切需要开发新的治疗apap诱导的ALF的方法。最近对动物模型和患者的研究表明，及时刺激先天肝再生与apap诱导的ALF的更好预后相关，包括无移植生存。这些研究表明，未经适当的肝再生，apap诱导的急性肝损伤可发展为ALF并导致死亡。尽管这些报道强调了APAP诱导ALF后肝脏再生的治疗潜力，但APAP过量后肝脏再生的机制尚不完全清楚。我们的初步研究表明，典型Wnt信号最终导致ß-catenin激活，在APAP诱导的ALF后的肝脏再生中起关键作用，并可用于治疗靶向。第一个具体目标的研究将确定典型Wnt通路的每个组分，包括ß-catenin、GSK3ß、disheveled、Lrp5和Wnt4在ALF后肝脏再生中的作用。开发ALF再生疗法的另一个重要问题是缺乏可靠且易于使用的肝脏再生生物标志物。目前，在ALF患者的血清中还没有可靠的、易于测量的生物标志物，可以揭示ALF患者先天肝再生的状态。考虑再生生物标志物的预测模型将使临床医生能够跟踪患者先天肝脏再生的状态，并有助于决定移植名单。我们的初步数据表明，血清白细胞来源的趋化素-2 （Lect2）水平可以作为急性肝衰竭后肝脏再生的可靠生物标志物。这些研究不仅将确定Lect2作为ALF再生的生物标志物的作用，还将确定Lect2在刺激肝细胞增殖中的作用，从而提供额外的治疗靶点。总的来说，本拨款提案中的研究将确定肝脏再生的机制，并确定apap诱导的ALF特异性肝脏再生的新生物标志物。这些研究的成功完成将对apap诱导的ALF患者的临床管理产生重大影响。

DESCRIPTION (provided by applicant): Overdose of acetaminophen (APAP), the popular analgesic and antipyretic agent, is the most common cause of acute liver failure (ALF) in the developing countries. Treatment options for APAP-induced ALF are extremely limited. Most ALF patients are treated with N-acetyl cystein, a precursor of glutathione, which works only if delivered within hours after APAP overdose. The only other therapy is liver transplantation, which is complicated by scarcity of donor organs, life long immunosuppressant use and exorbitant cost. There is a critical need to develop novel therapies for APAP-induced ALF. Recent studies in animal models and patients have demonstrated that timely stimulation of innate liver regeneration is associated with better outcomes including transplant free survival in APAP-induced ALF. These studies indicate that without proper liver regeneration APAP-induced acute liver injury can develop into ALF and result in death. Whereas these reports have underscored the therapeutic potential of liver regeneration following APAP-induced ALF, the mechanisms of liver regeneration after APAP overdose are not completely known. Our preliminary studies indicate that canonical Wnt signaling culminating in ß-catenin activation plays a critical role in liver regeneration after APAP- induced ALF and could be used for therapeutic targeting. The studies in the first specific aim will determine the role of each component of canonical Wnt pathway including ß-catenin, GSK3ß, disheveled, Lrp5 and Wnt4 in liver regeneration after ALF. Another significant problem in developing regenerative therapies for ALF is the lack of reliable and easy to use biomarkers of liver regeneration. Currently, there are no reliable biomarkers that can be easily measured in serum of ALF patients, which can reveal the status of innate liver regeneration in ALF patients. Predictive models that factor in biomarkers of regeneration will allow clinicians to track status of patient's innate liver regeneration and aid in decisions on listing for transplantation. Our preliminary data indicate tha serum levels of leukocyte derived chemotaxin-2 (Lect2) could be used as a reliable biomarker of liver regeneration following acute liver failure. These studies will not only determine the role of Lect2 as a biomarker of regeneration in ALF but also determine role of Lect2 in stimulation of hepatocyte proliferation providing an additional therapeutic target. Overall, the studies in this grant proposal will determine the mechanisms of liver regeneration and identify novel biomarkers of liver regeneration specific to APAP-induced ALF. Successful completion of these studies will have substantial impact on clinical management of APAP-induced ALF patients.