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 肝切除（即部分肝切除术； PHX）是一种常见的手术程序，用于治疗多重 肝病的形式，包括去除由肝癌引起的肿瘤和转移。肝脏可以 再生以恢复正常的肝功能，可确保大多数患者无并发症的恢复。 但是，许多患者遭受肝脏再生失败导致严重并发症， 包括肝后肝衰竭（PHLF），肝残余无法维持关键的情况 肝功能。肝切除后PHLF发展的生物标志物并非普遍预测。 更重要的是，尚无靶向疗法来刺激肝脏再生。该建议寻求 发现创新策略以更好地预测PHLF并同时发现新颖的假定治疗性 促进PHX患者肝脏再生的靶标。我们强烈的初步结果，产生 在小鼠中使用实验性PHX，术中肝脏和来自肝切除患者的血浆样品 一个定义明确的存储库，表明肝内血液凝血的快速激活是中心 肝脏再生的决定因素。具体而言，我们假设在形成的交联纤维蛋白聚合物 由于凝血活性的增加而导致的残留肝脏，促进肝血小板积累 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 立即可用的人肝和血浆样品中的血小板，以前精确收集 手术肝切除期间的序列，纤维蛋白（OGE）结构的综合机理评估和 实验和临床肝切除样品中的止血功能，表达遗传改性的小鼠 具有特定功能突变的纤维蛋白（OGEN）蛋白，将失败再生的全面分析与 肝功能障碍，以及FDA批准的纤维蛋白原浓缩物的应用 治疗性。调查团队包括国际认可的研究人员和医师科学家 在肝病中的凝血联系。调查团队在机械方面的专业知识的综合知识 肝损伤和再生，凝结和纤维蛋白（OGEN）生物化学/功能的研究以及前沿 临床/翻译研究最大程度地提高了所提出的研究的影响。在我们提出的研究中，我们将： （AIM 1）确定PHX后血液凝结与肝脏再生的机制； （目标2）识别 肝切除后患者的纤维蛋白原止血功能的修饰；和（目标 3）确定补充纤维蛋白原作为实验中新型促再生疗法的潜力 phx。这些特定目的的预期结果是发现了一种新型机械联系 凝结和肝脏再生。拟议的研究具有可能性的变革性，因为它们将 建议可以测量血液凝血的变化，主要认为是手术的继发性手术，并且 通过治疗控制，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.

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

• 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

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