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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结