Novel strategies to accelerate repair of drug-induced hepatotoxicity

加速修复药物引起的肝毒性的新策略

• 批准号: 10718314
• 负责人: James P Luyendyk
• 金额: $ 58.79万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718314
• 关键词: ADAMTS; Acceleration; Acetaminophen; Acute Liver Failure; Adhesions; Adhesives; Analgesics; Basic Science; Binding; Biological Markers; Blood Platelets; Cessation of life; Chimeric Proteins; Clinical; Clinical Research; Complex; Creativeness; Cytolysis; Data; Deposition; Engineering; Enzymes; FDA approved; Fibrinolytic Agents; Genetic; Goals; Hemorrhage; Hemostatic Agents; Hemostatic function; Hepatic; Hepatotoxicity; Human; Intensive Care; Link; Liver; Liver Failure; Liver diseases; Measures; Mediating; Molecular; Mus; Outcome; Overdose; Pathologic; Patients; Peptide Hydrolases; Physicians; Plasma; Plasma Proteins; Plasmin; Platelet Aggregation Inhibition; Prognosis; Publishing; Recombinants; Recovery; Research; Resolution; Rest; Risk; Role; Sampling; Scientist; Signal Transduction; System; Testing; Therapeutic; Thrombus; Tranexamic Acid; Translational Research; United States; acetaminophen-induced liver injury; acute liver injury; clinical application; clinical development; clinical translation; cohort; design; drug induced liver injury; gain of function; inhibiting antibody; injury and repair; innovation; intrahepatic; liver injury; liver repair; liver transplantation; loss of function; mutant; nanobodies; novel; novel marker; novel strategies; pharmacologic; platelet aggregating factor; prevent; programs; receptor; repaired; targeted treatment; therapeutic target; thrombolysis; translational potential; von Willebrand Disease; von Willebrand Factor

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.

项目摘要 止痛药对乙酰氨基酚（APAP）引起的急性肝损伤是 美国急性肝损伤。在许多情况下，肝脏修复失败会导致急性肝损伤持续 这可以发展为急性肝衰竭（ALF）。急性肝损伤和ALF的预后差，很少 重症监护以外的治疗选择。在过去的十年中，一些研究强调了如何 止血系统的变化与ALF的进展有关。例如，在 血小板粘合剂蛋白von Willebrand因子（VWF）及其主要调节酶ADAMTS13具有 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抑制了对APAP造成的肝脏的修复。强烈的初步结果 VWF或ADAMTS13中缺乏缺陷的小鼠，领先的VWF靶向治疗和人类ALF 样品表明VWF抑制了APAP诱导的肝损伤的分辨率。根据我们出版的 初步研究，我们的核心假设是肝VWF沉积抑制了APAP-的分辨率 通过形成肝内VWF - 斑点微杆菌的诱导肝损伤。我们的方法包括 基因改性的小鼠，临床发育中的VWF靶向分子，旨在保持的新型分子 VWF处于静止状态，新颖的VWF靶向溶栓药。这些研究与 我们试图发现以VWF为重点的生物标志物作为肝修复的新型生物标志物的创造性分析 来自ALF研究组提供的大型，良好的队列的样品的结果。这 调查团队代表了VWF专家的止血和肝病专家的最佳配对 和溶栓以及高度协作的医师科学家，增加了我们的研究的影响 翻译的潜力。我们提出的研究将确定ADAMTS13和VWF多聚体在 APAP引起的肝损伤和修复（AIM 1），确定将VWF连接到抑制肝修复的机制 在APAP挑战（AIM 2）之后，并确定将病理VWF沉积降解加速降解的策略 增强损伤肝脏的修复（AIM 3）。这些具体目标的预期结果是 发现新型机制，从而抑制受伤的肝脏的修复。这个结果将使 对现场的重大影响，因为它将为临床关联提供新的机械细节 在急性肝损伤的VWF和不良结果之间。拟议的研究具有变革性和预期 提供临床适用的策略以加速肝脏的维修 实验和转化科学由具有临床和基础研究专业知识的团队支持。