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: 10642950
• 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/10642950
• 关键词: Afibrinogenemia; 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; Glutaminase; Goals; Hemostatic function; Hepatectomy; Hepatic; Hour; Human; Integrin Inhibition; Integrins; International; Link; Liver; Liver Dysfunction; Liver Failure; Liver Regeneration; Liver diseases; Liver neoplasms; Malignant neoplasm of liver; Measures; Metastatic Neoplasm to the Liver; Modification; Mus; Mutation; Natural regeneration; Operative Surgical Procedures; Outcome; Partial Hepatectomy; Pathology; Patient Care; Patients; 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; Translational Research; Wild Type Mouse; 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; pharmacologic; 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.

项目摘要 肝脏切除术（即，部分肝切除术（PHx）是一种常见的外科手术， 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，确保大多数患者的无并发症恢复。 然而，相当多的患者患有肝再生失败，导致严重的并发症， 包括肝切除术后肝功能衰竭（PHLF），这是一种肝脏残余不能维持临界状态的情况， 肝功能肝切除术后PHLF发展的生物标志物并不能普遍预测。 更重要的是，没有靶向治疗可用于刺激肝再生。该提案寻求 发现创新的策略，以更好地预测PHLF，同时发现新的假定治疗 靶向促进PHx患者的肝再生。我们强大的初步结果，产生 使用小鼠中的实验性PHx和来自肝切除患者的术中肝脏和血浆样品， 一个明确的储存库，表明肝内凝血的快速激活是一个中心的， 肝再生的决定因素。具体地说，我们假设，交联的纤维蛋白聚合物，形成在 残肝由于凝血活性增加，促进肝血小板聚集， 刺激肝脏再生。我们的方法包括对纤维蛋白原与纤维蛋白原之间的相互作用进行创新性分析。 和血小板在立即可用的人肝脏和血浆样品，以前收集的精确 手术肝切除术期间的序列，纤维蛋白（原）结构的综合机制评估， 在实验和临床肝切除样品中的止血功能，基因修饰小鼠表达 具有特定功能突变的纤维蛋白（原）蛋白，将再生失败与 肝功能不全和FDA批准的纤维蛋白原浓缩物作为新的促再生剂的应用 有治疗作用的调查小组由国际公认的研究人员和医生科学家组成 肝脏疾病中凝血的联系。调查小组在机械方面的综合专长 研究肝损伤和再生，凝血和纤维蛋白（原）生物化学/功能， 临床/翻译研究最大限度地发挥了拟议研究的影响。在我们拟议的研究中，我们将： (Aim 1）确定PHx后血液凝固与肝再生之间的联系机制;（目的2） 纤维蛋白原止血功能的改变与肝切除术后患者的结局有关;（目的 3)确定纤维蛋白原补充作为实验性再生疗法的潜力 PHx。这些具体目标的预期结果是发现了一种新的机制联系， 凝血和肝再生。拟议的研究具有潜在的变革性，因为它们将 这表明，血液凝固的变化，主要被认为是继发于手术，可以测量， 治疗控制，以推动患者康复并预防肝衰竭。

项目成果

Intrahepatic neutrophil accumulation and extracellular trap formation are associated with posthepatectomy liver failure.

• DOI: 10.1097/hc9.0000000000000348
• 发表时间: 2024-01-01
• 期刊: Hepatology communications
• 影响因子: 5.1

Comparison of DLin-MC3-DMA and ALC-0315 for siRNA Delivery to Hepatocytes and Hepatic Stellate Cells.

• DOI: 10.1021/acs.molpharmaceut.2c00033
• 发表时间: 2022-07-04
• 期刊: MOLECULAR PHARMACEUTICS
• 影响因子: 4.9
• 作者: Ferraresso, Francesca;Strilchuk, Amy W.;Juang, Lih Jiin;Poole, Lauren G.;Luyendyk, James P.;Kastrup, Christian J.
• 通讯作者: Kastrup, Christian J.

Transcriptomic landscapes of effective and failed liver regeneration in humans.

人类有效和失败肝再生的转录组景观。

• DOI: 10.1016/j.jhepr.2023.100683
• 发表时间: 2023-04
• 期刊: JHEP REPORTS
• 影响因子: 8.3
• 作者: Starlinger, Patrick;Brunnthaler, Laura;McCabe, Chantal;Pereyra, David;Santol, Jonas;Steadman, Jessica;Hackl, Matthias;Skalicky, Susanna;Hackl, Hubert;Gronauer, Raphael;O'Brien, Daniel;Kain, Renate;Hirsova, Petra;Gores, Gregory J.;Wang, Chen;Gruenberger, Thomas;Smoot, Rory L.;Assinger, Alice
• 通讯作者: Assinger, Alice

Immunological Aspects of AXL/GAS-6 in the Context of Human Liver Regeneration.

在人肝脏再生的背景下，AXL/GAS-6的免疫学方面。

• DOI: 10.1002/hep4.1832
• 发表时间: 2022-03
• 期刊: Hepatology communications
• 影响因子: 5.1
• 作者: Ortmayr G;Brunnthaler L;Pereyra D;Huber H;Santol J;Rumpf B;Najarnia S;Smoot R;Ammon D;Sorz T;Fritsch F;Schodl M;Voill-Glaninger A;Weitmayr B;Födinger M;Klimpfinger M;Gruenberger T;Assinger A;Mikulits W;Starlinger P
• 通讯作者: Starlinger P

Hemostasis and Liver Regeneration.

• DOI: 10.1055/s-0040-1715450
• 发表时间: 2020-09
• 期刊: Seminars in thrombosis and hemostasis
• 影响因子: 5.7
• 作者: Starlinger P;Luyendyk JP;Groeneveld DJ
• 通讯作者: Groeneveld DJ