Novel anti-fibrotic mechanisms in chemical-induced liver injury

化学性肝损伤的抗纤维化新机制

基本信息

批准号：
8963788
负责人：
James P Luyendyk
金额：
$ 33.96万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8963788
关键词：
Accounting Address Adoptive Transfer Binding Biochemistry Blocking Antibodies Blood Blood coagulation Cell Adhesion Cell Culture System Cell physiology Cells Cessation of life Chemicals Chronic Cicatrix Coagulation Process Collagen Complement Data Deposition Development Drug Targeting Fibrin Fibrinogen Fibrosis Goals Hemorrhage Hepatic Human Immune In Vitro Inflammation Integrin Binding Integrins Interferons Lead Left Leukocytes Link Liver Liver Failure Liver Fibrosis Liver diseases Malignant Neoplasms Mediating Mediator of activation protein Mus Mutation NK Cell Activation Natural Killer Cells Outcome Pathogenesis Pathologic Pathway interactions Patients Peptide Hydrolases Polymers Production Proteins Publishing Reporting Research Resolution Risk Role Severities Signal Transduction Source Testing Therapeutic Thrombin Tissues Transgenic Organisms Translations Work Xenobiotics base cell injury chronic liver disease cytokine design effective therapy fibrinmonomer in vivo innovation insight liver function liver inflammation liver injury liver transplantation mouse model mutant new therapeutic target novel programs public health relevance research study small molecule surface coating targeted treatment therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Liver fibrosis is a devastating outcome of numerous liver diseases associated with xenobiotic exposure, and accounts for approximately one million deaths annually owing to liver failure and certain cancers. Patients with liver fibrosis would most likely benefit from therapies aimed at maximizing activity of endogenous anti-fibrotic pathways, such as natural killer (NK) cell activation, in order to delay the onset of liver failure. Increase activity of the blood coagulation cascade and conversion of soluble fibrinogen to insoluble fibrin polymers in liver are prominent features of liver fibrosis in humans and experimental xenobiotic-induced liver fibrosis in mice. Although frequently implicated as pathologic, an increase in tissue fibrin deposition is not synonymous with increasing fibrotic changes (i.e., collagen deposition). Indeed, the exact role of fibrin polymer deposition in the pathogenesis of liver fibrosis is largel unknown. Our strong preliminary analysis supports the novel concept that fibrin polymer has an inhibitory effect on fibrosis development in the liver. Identifying the precise role of fibrin polyers in liver fibrosis is critical, because this could reveal specific functions of fibrin polymers as putative therapeutic targets to treat liver fibrosis. Our strong preliminary studies suggest that fibrin polymers inhibit xenobiotic-induced liver fibrosis in mice by engaging specific cellular integrin's. The central hypothesis framing these studies is that fibrin polymers inhibit liver fibrosis by engaging the integrin aMß2 on resident liver NK cells to enhance their expression of anti-fibrotic mediators. Our approach includes genetically-modified mice expressing fibrinogen proteins with specific functional mutations, a unique primary NK cell culture system to study in vitro cell activation by fibrin, and a novel small molecule that allosterically enhances aMß2-dependent cell adhesion to fibrin polymers. The investigative team comprises experts in toxic liver injury and fibrosis, coagulation and fibrinogen biochemistry/function, and novel mouse models. Specifically, in our proposed studies we will: (Aim 1) Determine the mechanism by which fibrin inhibits experimental liver fibrosis; (Aim 2) Determine the mechanisms whereby fibrin enhances NK cell activation in vitro; and (Aim 3) Determine the contribution of the fibrin-NK cell axis to experimental liver fibrosis in vivo. The insights gained will significantly advance the current understanding of coagulation in liver fibrosis and highlight putative targets and novel therapeutic strategies to inhibit liver fibrosis. Potential strategies could include mechanism-based translation of drugs targeting specific non-hemostatic functions of fibrin that could reduce fibrosis without simultaneously inducing a bleeding risk.

描述（由适用提供）：肝纤维化是与异种生物暴露有关的多种肝病的毁灭性结果，由于肝衰竭和某些癌症，每年约为一百万人死亡。肝纤维化患者最多旨在最大化内源性抗纤维化途径活性的疗法，例如天然杀伤（NK）细胞激活，以延迟肝衰竭的发作。肝脏中血液凝结级联反应和固体纤维蛋白聚合物的转化的增加是人类肝纤维化的显着特征，而实验性异种生物学诱导的小鼠肝纤维化则是小鼠。尽管经常被视为病理，但组织增加纤维蛋白沉积不是增加纤维化变化（即胶原沉积）的代名词。实际上，纤维蛋白聚合物沉积在肝纤维化发病机理中的确切作用是很大的未知。我们强大的初步分析支持了一个新的概念，即纤维蛋白聚合物对肝脏中纤维化的发展具有抑制作用。识别纤维蛋白多素在肝纤维化中的确切作用至关重要，因为这可以揭示纤维蛋白聚合物的特定功能是治疗肝纤维化的假定治疗靶标。我们的强大初步研究表明，纤维蛋白聚合物通过参与特定的细胞整合蛋白而抑制了异生元诱导的小鼠肝纤维化。这些研究的中心假设是纤维蛋白聚合物通过与居民肝脏NK细胞的整合素AMß2接合以增强其抗纤维化介质的表达来抑制肝纤维化。我们的方法包括表达具有特定功能突变的纤维蛋白原蛋白的转基因小鼠，一种独特的原代NK细胞培养系统，研究纤维蛋白的体外细胞活化以及一种新型的小分子，可在变构增强AMß2依赖性细胞粘附到纤维蛋白聚合物。调查小组包括有毒肝损伤和纤维化，凝结和纤维蛋白原生物化学/功能的专家以及新型小鼠模型。具体而言，在我们提出的研究中，我们将：（目标1）确定纤维蛋白抑制实验性肝纤维化的机制；（AIM 2）确定纤维蛋白在体外增强NK细胞活化的机制；（目标3）确定纤维蛋白-NK细胞轴对体内实验性肝纤维化的贡献。获得的见解将大大提高当前对肝纤维化凝血的理解和突出了推定的靶标和新颖的靶标抑制肝纤维化的治疗策略。潜在的策略可以包括基于机制的基于机制的药物的翻译，该药物靶向纤维蛋白的特定非震动功能，这些药物可以减少纤维化，而不会简单地引起出血风险。