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

描述（由申请人提供）：慢性肝病是第12大死亡原因，也是美国最常见的发病原因之一，有550万人患有这种疾病。肝脏具有巨大的自我再生能力，但这种能力在患病的肝脏中大大降低，使得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治疗非常有限，因此需要替代疗法。增强先天性肝再生可以是一种替代疗法，因为它可以减轻疾病并改善生活质量。在先天性肝再生过程中，再生肝细胞可以来源于预先存在的肝细胞或胆管上皮细胞（BEC）。当肝细胞驱动的肝再生受损时，就会发生BEC驱动的肝再生，这是慢性肝病患者的情况。在患者中，BEC驱动的肝再生似乎已经启动，但未能完成B。了解BEC驱动的肝再生的整个过程应该为如何在肝脏患者中完成这一过程提供重要的见解。因此，我们开发了一种创新的斑马鱼肝再生模型，其中再生的肝细胞完全来自BEC。使用这个模型，我们发现，BMP信号的药理学抑制损害了BEC驱动的肝再生。基于我们的初步研究，我们假设Bmp信号在BEC驱动的肝再生中起着多种作用。我们将通过以下三个具体目标来检验这一假设。目的 一曰：我们将通过测试我们的工作假设来描述我们的斑马鱼模型中BEC驱动的肝再生的时间特征：BEC首先增殖，去分化成成肝细胞样细胞，相当于啮齿动物肝损伤模型中的卵圆细胞，然后再分化成肝细胞，肝细胞积极增殖以恢复肝脏质量。目标二：我们将通过在肝细胞消融和肝再生过程中的不同时间窗阻断或增强Bmp信号，并通过检查smad5突变体中的BEC驱动的肝再生，来确定Bmp信号在BEC驱动的肝再生中的作用。目标3：我们将确定Id2a，转录因子的分化抑制剂家族的成员，这是已知的Bmp信号在几个组织中的直接目标，在BEC驱动的肝再生中的作用，通过测试的工作假设，Id2a介导的Bmp信号对BEC驱动的肝再生的影响。该研究的完成将为揭示Bmp信号调控BEC驱动的肝再生机制提供新的思路。此外，他们将为如何在慢性肝病患者中增强和完成BEC驱动的肝再生提供新的见解。

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.