Delineating Molecular Mechanisms Underlying Liver Progenitor Cell-Driven Liver Regeneration

描绘肝脏祖细胞驱动的肝脏再生的分子机制

基本信息

批准号：
9910388
负责人：
Satdarshan Singh Monga
金额：
$ 54.14万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910388
关键词：
Alternative Therapies Apoptosis Biliary Cell Count Cell Differentiation process Data Disease EGFR inhibition Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Cells Erlotinib Event Exhibits Fibrosis Fishes Hepatic Mass Hepatocyte Inflammation Inflammatory Liver Liver Regeneration Liver diseases Mammals Mediating Modeling Molecular Morbidity - disease rate Mus Mutant Strains Mice Natural regeneration Oncogenes Patients Pharmaceutical Preparations Prevalence Process Proliferating Reaction Recovery Research Role Screening procedure Severity of illness Signal Transduction Testing Therapeutic Time Work Zebrafish base beta catenin chronic liver disease chronic liver injury cytokine effective therapy in vivo inhibitor/antagonist insight liver cell proliferation liver function liver injury liver repair liver transplantation mortality mouse model mutant oval cell overexpression regenerative regenerative agent regenerative therapy senescence small molecule stem cells

项目摘要

Abstract Chronic liver diseases are the 12th leading cause of mortality and among the most common causes of morbidity in the U.S. with 5.5 million people suffering from the diseases. Currently, liver transplantation is the only effective treatment for end-stage liver diseases; however, the shortage of donor livers makes this therapy extremely limited, thus necessitating alternative therapies. Promoting innate liver regeneration in chronic liver diseases is an attractive alternative. Upon liver injury, hepatocytes proliferate to yield more hepatocytes to restore lost liver mass and maintain liver function. However, when hepatocyte proliferation is compromised, a phenomenon observed in advanced liver diseases, liver progenitor cells (LPCs) are activated and these LPCs expand and eventually differentiate into hepatocytes. Thus, it is crucial to understand the molecular mechanisms of LPC- driven liver regeneration, which will provide significant insights into promoting this process as a pro-regenerative therapy for advanced liver diseases. Particularly, given the prevalence of LPCs in chronically diseased livers, promoting LPC differentiation into functional hepatocytes will be a promising pro-regenerative therapy. We have established a zebrafish liver injury model in which hepatocyte-specific overexpression of oncogenes induces oncogene-induced hepatocyte damage, such as senescence and apoptosis, followed by inflammation, LPC activation, fibrosis and eventually LPC-mediated liver repair. Using this chronic liver injury model as a screening tool for identifying small molecules that can promote LPC differentiation into hepatocytes, we discovered that treatment with EGFR inhibitors promoted LPC differentiation into hepatocytes, thereby enhancing liver repair/recovery. In addition to the zebrafish model, we have established a mouse liver injury model for LPC- driven liver regeneration. This mouse model allows us to determine if EGFR inhibition can promote LPC differentiation into hepatocytes in mammals as in fish. Here, we propose to determine the effect of EGFR inhibition on LPC differentiation and the role of EGFR signaling in LPC-driven liver regeneration by pursuing three specific aims. Aim 1: Using two zebrafish models of hepatocyte-specific oncogene overexpression, we will elucidate the process of LPC-driven liver regeneration in oncogene-induced liver damage settings. Aim 2: Using the zebrafish and mouse liver injury models for LPC-driven liver regeneration, we will determine the effects of EGFR inhibition on LPC differentiation into hepatocytes and subsequent liver recovery. Aim 3: We will determine the molecular mechanisms controlling LPC differentiation by investigating the role of EGFR and Sox9 in this differentiation process. Successful accomplishment of the proposed work will not only significantly advance the mechanistic understanding of liver regeneration in the diseased liver, but also lay the groundwork for use of EGFR inhibitors as a promising pro-regenerative agent to augment LPC-driven liver regeneration in patients with advanced liver diseases.

抽象的慢性肝病是第 12 大死亡原因，也是最常见的发病原因之一在美国，有 550 万人患有这种疾病。目前，肝移植是唯一有效的方法终末期肝病的治疗；然而，供体肝脏的短缺使得这种疗法极其困难。有限，因此需要替代疗法。促进慢性肝病的先天性肝再生是一个有吸引力的选择。肝损伤后，肝细胞增殖产生更多肝细胞来恢复失去的肝脏质量和维持肝功能。然而，当肝细胞增殖受到损害时，就会出现一种现象在晚期肝脏疾病中观察到，肝祖细胞 (LPC) 被激活，并且这些 LPC 会扩张并最终分化为肝细胞。因此，了解 LPC 的分子机制至关重要。驱动肝脏再生，这将为促进这一过程作为促再生提供重要的见解治疗晚期肝脏疾病。特别是考虑到 LPC 在慢性疾病肝脏中的普遍存在，促进LPC分化为功能性肝细胞将是一种有前途的促再生疗法。我们有建立了斑马鱼肝损伤模型，其中癌基因的肝细胞特异性过度表达诱导癌基因诱导的肝细胞损伤，如衰老和凋亡，随后发生炎症、LPC 激活、纤维化以及最终 LPC 介导的肝脏修复。使用这种慢性肝损伤模型作为筛选鉴定可促进 LPC 分化为肝细胞的小分子的工具，我们发现 EGFR抑制剂治疗促进LPC分化为肝细胞，从而增强肝脏功能修复/恢复。除了斑马鱼模型外，我们还建立了LPC-小鼠肝损伤模型驱动肝脏再生。该小鼠模型使我们能够确定 EGFR 抑制是否可以促进 LPC 哺乳动物和鱼类中分化为肝细胞。在这里，我们建议确定EGFR的作用通过追求对 LPC 分化的抑制以及 EGFR 信号在 LPC 驱动的肝再生中的作用三个具体目标。目标 1：使用两种肝细胞特异性癌基因过度表达的斑马鱼模型，我们将阐明癌基因诱导的肝损伤环境中 LPC 驱动的肝再生过程。目标 2：使用斑马鱼和小鼠肝损伤模型对 LPC 驱动的肝再生的影响，我们将确定 EGFR 抑制 LPC 分化为肝细胞以及随后的肝脏恢复。目标 3：我们将确定通过研究 EGFR 和 Sox9 在此过程中的作用，了解控制 LPC 分化的分子机制分化过程。拟议工作的成功完成不仅将显着推进对患病肝脏中肝再生的机制的了解，也为使用 EGFR 抑制剂作为一种有前途的促再生剂，可增强 LPC 驱动的肝再生患者晚期肝脏疾病。