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.

抽象的 慢性肝疾病是死亡率的第12个主要原因，也是发病率最常见的原因之一 在美国，有550万人患有疾病。目前，肝移植是唯一有效的 治疗末期肝病；但是，供体肝脏的短缺使这种疗法极为 有限，因此需要替代疗法。促进慢性肝病中的先天肝脏再生是 一个有吸引力的选择。肝损伤后，肝细胞扩散以产生更多的肝细胞以恢复肝脏 质量并保持肝功能。但是，当肝细胞增殖受到损害时，一种现象 在晚期肝病中观察到的肝脏祖细胞（LPC）被激活，这些LPC扩展，并且 最终分化为肝细胞。因此，了解LPC-的分子机制至关重要 驱动的肝脏再生将为促进这一过程提供重要的见解 晚期肝病的治疗。特别是，鉴于长期患病的肝脏中LPC的患病率， 促进LPC分化为功能性肝细胞将是一种有希望的促进疗法。我们有 建立了斑马鱼肝损伤模型，其中肝细胞特异性的过表达诱导 癌基因诱导的肝细胞损伤，例如衰老和凋亡，随后炎症，LPC 激活，纤维化和最终LPC介导的肝修复。使用这种慢性肝损伤模型作为筛查 用于识别可以促进LPC分化为肝细胞的小分子的工具，我们发现 用EGFR抑制剂治疗将LPC分化为肝细胞，从而增强肝脏 维修/恢复。除斑马鱼模型外，我们还为LPC-建立了小鼠肝损伤模型 驱动的肝脏再生。该鼠标模型允许我们确定EGFR抑制是否可以促进LPC 与鱼类一样，分化为哺乳动物的肝细胞。在这里，我们建议确定EGFR的影响 抑制LPC分化以及EGFR信号在LPC驱动的肝脏再生中的作用 三个具体目标。 AIM 1：使用肝细胞特异性癌基因过表达的两种斑马鱼模型，我们将 阐明了癌基因诱导的肝损伤环境中LPC驱动的肝脏再生的过程。目标2：使用 斑马鱼和小鼠肝损伤模型用于LPC驱动的肝脏再生，我们将确定 EGFR抑制LPC分化为肝细胞和随后的肝脏回收。目标3：我们将确定 通过研究EGFR和SOX9在此中的作用来控制LPC分化的分子机制 分化过程。成功完成拟议的工作不仅会显着促进 对患病肝脏肝脏再生的机械理解，但也为使用的基础奠定了基础 EGFR抑制剂是一种有前途的促再生剂，可增强LPC驱动的肝脏再生患者 晚期肝病。