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

描述(申请人提供)：慢性肝病是导致死亡的第12位主要原因，也是美国最常见的致病原因之一，美国有550万人患有这种疾病。肝脏具有巨大的自我再生能力，但在患病的肝脏中，这种能力大大降低，使肝移植成为治疗终末期慢性肝病的唯一有效方法。然而，供体肝脏的短缺使这种疗法极其有限，因此有必要进行替代疗法。增强先天肝脏再生可以作为一种替代疗法，因为它可以缓解疾病，提高生活质量。在先天肝再生过程中，再生的肝细胞可以来源于先前存在的肝细胞或胆管上皮细胞。当肝细胞驱动的肝再生受到损害时，就会发生BEC驱动的肝再生，慢性肝病患者就是这种情况。在患者中，似乎启动了BEC驱动的肝再生，但未能完成。了解BEC驱动的肝脏再生的整个过程将为如何在肝脏患者中完成这一过程作为治疗方法提供重要的见解。因此，我们开发了一种创新的斑马鱼肝再生模型，在该模型中，再生的肝细胞完全来源于BEC。使用这个模型，我们发现BMP信号的药物抑制损害了BEC驱动的肝再生。根据我们的初步研究，我们假设BMP信号在BEC驱动的肝再生中扮演多种角色。我们将通过追求以下三个具体目标来检验这一假设。目标 1：我们将通过检验我们的工作假说来描述斑马鱼模型中BEC驱动的肝再生的时间特征：BEC首先增殖，去分化为肝母细胞样细胞，相当于啮齿动物肝损伤模型中的卵圆形细胞，然后重新分化活跃增殖的肝细胞以恢复肝脏质量。目的2：通过在肝细胞消融和肝再生的不同时间窗阻断或增强BMP信号，以及通过检测Smad5突变体中BMP信号在BEC驱动的肝再生中的作用，我们将确定BMP信号在BEC驱动的肝再生中的作用。目的：通过验证Id2a介导BMP信号在BEC诱导的肝再生中的作用假说，我们将确定转录因子分化抑制因子家族的成员Id2a在多个组织中BMP信号的直接靶点--BEC诱导的肝再生中的作用。这项拟议工作的完成将通过揭示BMP信号调节BEC驱动的肝再生的机制，显著促进肝再生领域的发展。此外，他们将为如何增强和完成BEC驱动的慢性肝病患者的肝再生作为治疗方法提供新的见解。

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.