Novel strategies to accelerate repair of drug-induced hepatotoxicity

项目总结 过量服用止痛药对乙酰氨基酚(APAP)引起的急性肝损伤是 美国的急性肝脏损伤。在许多情况下，肝修复失败会导致急性肝损伤持续存在。 这可能会发展为急性肝功能衰竭(ALF)。急性肝损伤和ALF的预后很差， 重症监护以外的治疗选择。在过去的十年里，几项研究强调了 止血系统的改变与ALF的进展有关。例如，经济中的失衡 血小板黏附蛋白von Willebrand因子及其主要调节酶ADAMTS13 已被确定为ALF患者肝移植和死亡风险增加的独特指标。我们的 已发表的研究表明，VWF抑制APAP损伤的肝脏修复。强劲的初步结果使用 缺乏VWF或ADAMTS13、前沿VWF靶向疗法和人类ALF的小鼠 样本提示，VWF抑制APAP诱导的肝损伤的消退。基于我们发布的和 初步研究，我们的中心假设是肝脏VWF沉积抑制APAP- 肝内VWF-血小板微血栓形成致肝损伤。我们的方法包括 转基因小鼠，临床开发中的VWF靶向分子，旨在保持 静息状态的VWF，以及新型VWF靶向溶栓药物。这些研究与以下内容密切相关 我们试图发现聚焦于VWF的生物标记物作为肝脏修复的新生物标记物的创造性分析 ALF研究小组提供的一个大型、特征良好的队列样本中的样本和结果。这个 调查团队代表了止血和肝病专家、VWF专家的最佳组合 和溶栓，以及高度合作的内科科学家，增加了我们研究和 翻译的潜力。我们建议的研究将确定ADAMTS13和VWF多聚体大小在 APAP诱导的肝损伤和修复(目标1)，确定VWF与抑制肝修复的机制 APAP攻击后(目标2)，并确定加速病理性VWF沉积降解的策略 加强APAP损伤肝脏的修复(目标3)。这些具体目标的预期结果是 发现vwf抑制受损肝脏修复的新机制。这一结果将使 对该领域产生重大影响，因为它将为临床关联提供新的机械细节 VWF与急性肝损伤预后不良之间的关系。拟议的研究具有变革性和预期性。 提供临床适用的策略，以加速肝脏修复，这是由于 实验和转化科学由一支拥有临床和基础研究专业知识的团队支持。

PROJECT SUMMARY Acute liver injury caused by overdose of the pain medication acetaminophen (APAP) is a leading cause of acute liver injury in the United States. In many cases, a failure of liver repair causes acute liver injury to persist and this can progress to acute liver failure (ALF). Acute liver injury and ALF have a poor prognosis and little therapeutic options beyond intensive care. Over the past decade, several studies have highlighted how changes in the hemostatic system are connected to the progression of ALF. For example, an unbalance in the platelet adhesive protein von Willebrand Factor (VWF) and its primary regulatory enzyme ADAMTS13 have been identified as unique indicators of increased risk for liver transplant and death in patients with ALF. Our published studies indicate that VWF inhibits repair of the APAP-injured liver. Strong preliminary results using mice with deficiencies in VWF or ADAMTS13, leading-edge VWF-targeted therapeutics, and human ALF samples suggest that VWF inhibits the resolution of APAP-induced liver injury. Based on our published and preliminary studies, our central hypothesis is that hepatic VWF deposition inhibits the resolution of APAP- induced liver injury through formation of intrahepatic VWF-platelet microthrombi. Our approach includes genetically-modified mice, VWF-targeted molecules in clinical development, novel molecules designed to hold VWF in a resting state, and novel VWF-targeted thrombolytic drugs. These studies are closely aligned with creative analyses in which we seek to uncover VWF-focused biomarkers as novel biomarkers of liver repair and outcome in samples from a large, well-characterized cohort provided by the ALF Study Group. The investigative team represents an optimal pairing of experts on hemostasis and liver disease, experts on VWF and thrombolysis, and highly collaborative physician-scientists, increasing the impact of our studies and potential for translation. Our proposed studies will determine the role of ADAMTS13 and VWF multimer size in APAP-induced liver injury and repair (Aim 1), determine the mechanisms linking VWF to inhibition liver repair after APAP challenge (Aim 2), and identify strategies to accelerate degradation of pathologic VWF deposits to enhance repair of the APAP-injured liver (Aim 3). The expected outcome of these Specific Aims is the discovery of novel mechanisms whereby VWF inhibits repair of the injured liver. This outcome would make a significant impact on the field because it would deliver novel mechanistic details for clinical associations between VWF and poor outcome in acute liver injury. The proposed studies are transformative and anticipated to deliver clinically applicable strategies to accelerate repair of the liver, owing to a strong combination of experimental and translational science backed by a team with clinical and basic research expertise.