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

• 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
• 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

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.

摘要 慢性肝病是第12大致死原因，也是最常见的致病原因之一。 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，供体肝脏的短缺使这种疗法变得非常 有限，因此有必要采用替代疗法。在慢性肝病中促进先天肝再生 这是一个有吸引力的选择。肝损伤后，肝细胞增殖，产生更多的肝细胞，恢复失去的肝脏 减轻体重，维持肝功能。然而，当肝细胞增殖受到损害时，一种现象 在晚期肝病中观察到，肝祖细胞(LPC)被激活，这些LPC扩张并 最终分化成肝细胞。因此，了解LPC的分子机制是至关重要的。 推动肝脏再生，这将为促进这一过程作为促再生提供重要的见解 晚期肝病的治疗。特别是，鉴于LPCS在慢性疾病肝脏中的普遍存在， 促进LPC向有功能的肝细胞分化将是一种有前景的促再生治疗方法。我们有 建立了斑马鱼肝细胞特异性过表达癌基因的肝损伤模型 癌基因引起的肝细胞损伤，如衰老和凋亡，随后是炎症，LPC 活化、纤维化，最终由LPC介导的肝修复。使用该慢性肝损伤模型作为筛选 用于鉴定可促进LPC向肝细胞分化的小分子的工具，我们发现 用EGFR抑制剂治疗可促进LPC分化为肝细胞，从而增强肝脏功能 修复/恢复。除斑马鱼模型外，我们还建立了LPC的小鼠肝损伤模型- 推动肝脏再生。这个小鼠模型使我们能够确定抑制EGFR是否可以促进LPC 哺乳动物分化成肝细胞，如鱼类。在这里，我们建议确定EGFR的效果 抑制LPC分化及EGFR信号转导途径在LPC促肝再生中的作用 三个具体目标。目的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 阐明在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 在斑马鱼和小鼠肝损伤模型中，我们将确定LPC驱动的肝再生的效果 EGFR抑制LPC向肝细胞分化和随后的肝恢复。目标3：我们将确定 通过研究EGFR和Sox9在LPC分化中的作用研究LPC分化的分子机制 分化过程。拟议工作的成功完成不仅将大大推进 从机理上了解肝脏再生在病变肝脏中的作用，同时也为使用 EGFR抑制剂作为一种有前景的促再生剂促进LPC驱动的肝再生 晚期肝病。