Mechanisms of Liver Regeneration After Acetaminophen-Induced Acute Liver Failure

描述(申请人提供)：过量的对乙酰氨基酚(APAP)，一种流行的止痛剂和解热剂，是发展中国家急性肝功能衰竭(ALF)的最常见原因。APAP所致ALF的治疗选择极其有限。大多数ALF患者使用N-乙酰半胱氨酸治疗，N-乙酰半胱氨酸是谷胱甘肽的前体，只有在APAP过量服药后几个小时内才起作用。唯一的其他治疗方法是肝移植，其复杂的问题是供体器官稀缺、终生使用免疫抑制剂和昂贵的费用。因此迫切需要开发新的治疗APAP所致ALF的方法。最近在动物模型和患者中的研究表明，及时刺激先天肝再生与更好的结果相关，包括APAP诱导的ALF的无移植生存。这些研究表明，如果没有适当的肝再生，APAP诱导的急性肝损伤可发展为ALF并导致死亡。虽然这些报道强调了APAP诱导的ALF后肝再生的治疗潜力，但APAP过量后肝再生的机制尚不完全清楚。我们的初步研究表明，规范的Wnt信号在APAP诱导的ALF后肝再生中起关键作用，并可用于靶向治疗。第一个特定目标的研究将确定典型的Wnt通路的各个组成部分在ALF后肝再生中的作用，包括？连环蛋白、GSK3？、Disheveled、LRP5和Wnt4。开发ALF再生疗法的另一个重要问题是缺乏可靠和易于使用的肝再生生物标志物。目前，还没有可靠的生物标志物可以方便地在ALF患者的血清中检测，从而揭示ALF患者的先天肝再生状态。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再生的状态，并帮助决定是否将其列入移植名单。我们的初步数据表明，血清白细胞衍生趋化蛋白-2(Lect2)水平可作为急性肝功能衰竭后肝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，为ALF的治疗提供新的靶点。总体而言，这项拨款提案中的研究将确定肝再生的机制，并识别APAP诱导的ALF特异性的新的肝再生生物标志物。这些研究的成功完成将对APAP诱导的ALF患者的临床治疗产生重大影响。

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.