Elucidating the Mechanisms by which Bmp Signaling Regulates Biliary-Driven Liver Regeneration

阐明 Bmp 信号调节胆道驱动的肝脏再生的机制

• 批准号: 9270021
• 负责人: Donghun Shin
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270021
• 关键词: Ablation; Alternative Therapies; Biliary; Bone Morphogenetic Proteins; Cells; Characteristics; Chronic; Data; Development; Differentiation Inhibitor; Disease; Epithelial Cells; Family; Genes; Genetic Transcription; Goals; Hepatic Mass; Hepatocyte; Impairment; Larva; Ligands; Link; Literature; Liver; Liver Regeneration; Liver diseases; Mediating; Modeling; Molecular; Morbidity - disease rate; Natural regeneration; Organ; Patients; Pharmacology; Play; Process; Proliferating; Publishing; Quality of life; Research; Rodent; Role; Severity of illness; Signal Pathway; Signal Transduction; Signaling Protein; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Work; Zebrafish; base; cell dedifferentiation; chronic liver disease; effective therapy; experimental study; improved; inhaled nitric oxide; innovation; insight; knock-down; liver function; liver injury; liver transplantation; loss of function; member; mortality; mutant; novel; oval cell; overexpression; public health relevance; regenerative; response; transcription factor

DESCRIPTION (provided by applicant): 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. The liver has an enormous capacity to regenerate itself, but this capacity is greatly reduced in the diseased liver, making liver transplantation the only effective treatment for end-stage chronic liver diseases. The shortage of donor livers however makes this therapy extremely limited, thus necessitating alternative therapies. Augmenting innate liver regeneration can be an alternative therapy because it may mitigate the diseases and improve the quality of life. During innate liver regeneration, regenerated hepatocytes can be derived from preexisting hepatocytes or biliary epithelial cells (BECs). BEC-driven liver regeneration occurs when hepatocyte-driven liver regeneration is compromised, which is the case in patients with chronic liver diseases. It appears that BEC-driven liver regeneration was initiated but failed to b complete in the patients. Understanding of the entire process of BEC-driven liver regeneration should provide significant insights into how to complete this process in liver patients as therapeutics. Thus, we developed an innovative zebrafish liver regeneration model in which regenerated hepatocytes are exclusively derived from BECs. Using this model, we found that pharmacological inhibition of Bmp signaling impaired BEC-driven liver regeneration. Based on our preliminary studies, we hypothesize that Bmp signaling plays multiple roles in BEC-driven liver regeneration. We will test this hypothesis by pursuing the following three specific aims. Aim 1: We will delineate temporal characteristics of BEC-driven liver regeneration in our zebrafish model by testing our working hypothesis: BECs first proliferate, dedifferentiate into hepatoblast-like cells, the equivalent of oval cells in rodent liver injury models, and then redifferentiate ino hepatocytes that actively proliferate to recover liver mass. Aim 2: We will determine the roles of Bmp signaling in BEC-driven liver regeneration, by blocking or enhancing Bmp signaling at distinct time-windows during hepatocyte ablation and liver regeneration and by examining BEC-driven liver regeneration in smad5 mutants. Aim 3: We will determine the role of Id2a, a member of the inhibitor of differentiation family of transcription factors, which is known to be the direc target of Bmp signaling in several tissues, in BEC-driven liver regeneration by testing the working hypothesis that Id2a mediates the effect of Bmp signaling on BEC-driven liver regeneration. The accomplishment of the proposed work will significantly advance the field of liver regeneration by revealing the mechanisms by which Bmp signaling regulates BEC-driven liver regeneration. Furthermore, they will provide novel insights into how to augment and complete BEC-driven liver regeneration in patients with chronic liver diseases as therapeutics.

描述（由申请人提供）：慢性肝脏疾病是死亡率的第12个主要原因，也是美国发病率最常见的原因之一，有550万人患有疾病。肝脏具有重生的巨大能力，但是患病的肝脏能力大大降低，使肝移植成为终末期慢性肝病的唯一有效治疗方法。然而，供体肝脏的短缺使得这种疗法极为有限，因此需要替代疗法。增加先天肝脏再生可能是一种替代疗法，因为它可以减轻疾病并改善生活质量。在先天肝脏再生过程中，再生的肝细胞可以源自先前存在的肝细胞或胆道上皮细胞（BEC）。当肝细胞驱动的肝脏再生受到损害时，发生BEC驱动的肝脏再生发生，在慢性肝病患者中就是这种情况。看来启动了由BEC驱动的肝脏再生，但未能完成患者的B完成。了解BEC驱动的肝脏再生过程的整个过程应提供有关如何在肝脏患者中作为治疗剂完成此过程的重要见解。因此，我们开发了一种创新的斑马鱼肝脏再生模型，其中再生的肝细胞仅来自BEC。使用该模型，我们发现BMP信号传导的药理抑制受BEC驱动的肝脏再生损害。根据我们的初步研究，我们假设BMP信号在BEC驱动的肝脏再生中起多种作用。我们将通过追求以下三个特定目标来检验这一假设。目的 1: We will delineate temporal characteristics of BEC-driven liver regeneration in our zebrafish model by testing our working hypothesis: BECs first proliferate, dedifferentiate into hepatoblast-like cells, the equivalent of oval cells in rodent liver injury models, and then redifferentiate ino hepatocytes that actively proliferate to recover liver mass. AIM 2：我们将通过在肝细胞消融和肝脏再生过程中阻止或增强BMP信号在不同的时间闪烁的BMP信号传导以及通过检查SMAD5突变体中的BEC驱动的肝脏再生，从而确定BMP信号传导在BEC驱动的肝脏再生中的作用。 AIM 3：我们将确定ID2A的作用，ID2A是转录因子分化家族抑制剂的成员，这是多个组织中BMP信号传导的目的靶标，在BEC驱动的肝脏再生中，通过测试ID2A介导BMP信号对BEC驱动的肝脏肝脏恢复的作用的工作假设。提议的工作的完成将通过揭示BMP信号调节BEC驱动的肝脏再生的机制，从而显着推动肝脏再生领域。此外，他们将提供有关如何增加慢性肝病患者作为治疗剂的患者的新见解。