Novel coagulation-dependent mechanisms of liver regeneration to detect and prevent liver dysfunction after partial hepatectomy

肝脏再生的新型凝血依赖性机制可检测和预防部分肝切除术后的肝功能障碍

• 批准号: 10202588
• 负责人: James P Luyendyk
• 金额: $ 40.79万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10202588
• 关键词: Biochemistry; Blood Coagulation Factor; Blood Platelets; Blood coagulation; Cessation of life; Clinical; Clinical Research; Coagulation Process; Complication; Deposition; Development; Ensure; Excision; FDA approved; Factor XIII; Failure; Fibrin; Fibrinogen; Functional disorder; Gap Junctions; Goals; Hemostatic function; Hepatectomy; Hepatic; Hour; Human; Integrins; International; Investigation; Link; Liver; Liver Dysfunction; Liver Failure; Liver Regeneration; Liver diseases; Liver neoplasms; Malignant neoplasm of liver; Measures; Modification; Mus; Mutation; Natural regeneration; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Partial Hepatectomy; Pathology; Patient Care; Patients; Pharmacology; Physicians; Plasma; Platelet aggregation; Polymers; Procedures; Proteins; Publishing; Recovery; Regenerative pathway; Regenerative response; Research; Research Personnel; Role; Sampling; Scientist; Secondary to; Structure; Supplementation; Testing; Therapeutic; Time; Tissues; Transglutaminases; Wild Type Mouse; base; biomarker development; crosslink; experimental study; genetic approach; improved; innovation; intrahepatic; liver biopsy; liver function; liver injury; mutant; new therapeutic target; novel; novel strategies; outcome prediction; platelet function; predictive marker; prevent; regenerative therapy; repository; targeted treatment; therapeutic target; tumor

PROJECT SUMMARY Resection of the liver (i.e., partial hepatectomy; PHx) is a common surgical procedure used to treat multiple forms of liver disease, including removal of tumors caused by liver cancer and metastases. The liver can regenerate to restore normal hepatic function, ensuring a complication-free recovery in most patients. However, a significant number of patients suffer from failed liver regeneration leading to serious complications, including post-hepatectomy liver failure (PHLF), a condition where the liver remnant cannot sustain critical hepatic functions. Biomarkers of the development of PHLF after liver resection are not universally predictive. More importantly, there are no targeted therapies available to stimulate liver regeneration. This proposal seeks to discover innovative strategies to better predict PHLF and simultaneously uncover novel putative therapeutic targets to promote liver regeneration in patients undergoing PHx. Our strong preliminary results, generated using experimental PHx in mice and intraoperative liver and plasma samples from liver resection patients from a well-defined repository, suggest that rapid activation of intrahepatic blood coagulation is a central determinant of liver regeneration. Specifically, we hypothesize that cross-linked fibrin polymers, formed in the remnant liver as a result of increased coagulation activity, promote hepatic platelet accumulation that stimulates liver regeneration. Our approach includes innovative analysis of the interplay between fibrinogen and platelets in immediately available human liver and plasma samples, previously collected in precise sequence during surgical liver resection, comprehensive mechanistic assessment of fibrin(ogen) structure and hemostatic functions in experimental and clinical liver resection samples, genetically-modified mice expressing fibrin(ogen) proteins with specific functional mutations, comprehensive analyses linking failed regeneration to hepatic dysfunction, and application of FDA-approved fibrinogen concentrates as a novel pro-regenerative therapeutic. The investigative team comprises internationally-recognized researchers and physician-scientists at the nexus of coagulation in liver disease. The combined expertise of the investigative team in mechanistic studies of liver injury and regeneration, coagulation and fibrin(ogen) biochemistry/function, and leading-edge clinical/translational investigation maximizes impact of the proposed studies. In our proposed studies we will: (Aim 1) Determine the mechanism linking blood coagulation to liver regeneration after PHx; (Aim 2) Identify modifications of fibrinogen hemostatic function connected to outcome in patients after liver resection; and (Aim 3) Determine the potential of fibrinogen supplementation as a novel pro-regenerative therapy in experimental PHx. The expected outcome of these Specific Aims is the discovery of a novel mechanistic link between coagulation and liver regeneration. The proposed studies are potentially transformative, because they would suggest that changes in blood coagulation, largely considered secondary to the surgery, can be measured and therapeutically controlled to drive patient recovery and prevent liver failure.

项目概要 肝脏切除术（即部分肝切除术；PHx）是一种常见的外科手术，用于治疗多发性肝癌 各种形式的肝脏疾病，包括切除由肝癌和转移引起的肿瘤。肝脏可以 再生以恢复正常的肝功能，确保大多数患者无并发症的康复。 然而，大量患者的肝再生失败，导致严重的并发症， 包括肝切除术后肝功能衰竭（PHLF），这是一种肝脏残余物无法维持危重状态的情况 肝功能。肝切除术后发生 PHLF 的生物标志物并不能普遍预测。 更重要的是，没有可用于刺激肝再生的靶向疗法。该提案寻求 发现更好地预测 PHLF 的创新策略，同时发现新的假定治疗方法 促进 PHx 患者肝再生的目标。我们产生了强有力的初步结果 在小鼠中使用实验性 PHx 以及来自肝切除患者的术中肝脏和血浆样本 一个明确的储存库表明，肝内凝血的快速激活是一个中心 肝再生的决定因素。具体来说，我们假设交联的纤维蛋白聚合物在 残肝由于凝血活性增加，促进肝内血小板聚集， 刺激肝脏再生。我们的方法包括对纤维蛋白原之间相互作用的创新分析 以及立即可用的人类肝脏和血浆样本中的血小板，这些样本之前以精确的方式收集 肝切除手术过程中的顺序、纤维蛋白（原）结构的综合机制评估和 实验和临床肝切除样本中的止血功能，转基因小鼠表达 具有特定功能突变的纤维蛋白（原）蛋白，综合分析将失败的再生与 肝功能障碍，以及 FDA 批准的纤维蛋白原浓缩物作为新型促再生药物的应用 治疗性的。研究团队由国际知名的研究人员和医师科学家组成 肝脏疾病中凝血的关系。调查团队在机械方面的综合专业知识 肝损伤和再生、凝血和纤维蛋白（原）生物化学/功能以及前沿研究 临床/转化研究最大限度地提高了拟议研究的影响。在我们提出的研究中，我们将： （目标1）确定PHx后凝血与肝再生之间的联系机制； （目标 2）识别 纤维蛋白原止血功能的改变与肝切除术后患者的预后相关；和（目标 3) 在实验中确定纤维蛋白原补充剂作为新型促再生疗法的潜力 PHx。这些具体目标的预期结果是发现之间的新颖机制联系 凝血和肝再生。拟议的研究具有潜在的变革性，因为它们将 表明凝血的变化（主要被认为是继发于手术的）可以测量和 治疗控制以促进患者康复并预防肝衰竭。