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: 8931956
• 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/8931956
• 关键词: Ablation; Alternative Therapies; Biliary; Bone Morphogenetic Proteins; Cells; Characteristics; Chronic; Data; Development; Differentiation Inhibitor; Disease; Epithelial Cells; Family; Genes; Goals; Health; Hepatic Mass; Hepatocyte; Larva; Ligands; Link; Literature; Liver; Liver Regeneration; Liver diseases; Mediating; Modeling; Molecular; Morbidity - disease rate; Natural regeneration; Organ; Patients; Play; Process; Proliferating; Publishing; Quality of life; Research; Rodent; Role; Severity of illness; Signal Pathway; Signal Transduction; Staging; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Work; Zebrafish; base; cell dedifferentiation; chronic liver disease; effective therapy; improved; innovation; insight; liver function; liver injury; liver transplantation; loss of function; member; mortality; mutant; novel; oval cell; overexpression; regenerative; research study; 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）：慢性肝病是美国第 12 大死亡原因，也是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疗法极其有限，因此需要替代疗法。增强先天性肝再生可以作为一种替代疗法，因为它可以减轻疾病并提高生活质量。在先天性肝再生过程中，再生的肝细胞可以源自先前存在的肝细胞或胆管上皮细胞（BEC）。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。看来 BEC 驱动的肝脏再生已在患者中启动，但未能完成。了解 BEC 驱动的肝脏再生的整个过程应该为如何在肝脏患者中完成这一过程作为治疗提供重要的见解。因此，我们开发了一种创新的斑马鱼肝脏再生模型，其中再生的肝细胞完全来源于 BEC。使用该模型，我们发现 Bmp 信号传导的药理抑制会损害 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 驱动的肝再生中发挥多种作用。我们将通过追求以下三个具体目标来检验这一假设。目的 图 1：我们将通过测试我们的工作假设，在斑马鱼模型中描绘 BEC 驱动的肝再生的时间特征：BEC 首先增殖，去分化为成肝细胞样细胞（相当于啮齿动物肝损伤模型中的卵形细胞），然后重新分化为积极增殖以恢复肝脏质量的肝细胞。目标 2：我们将通过在肝细胞消融和肝脏再生期间的不同时间窗口阻断或增强 Bmp 信号传导，并通过检查 smad5 突变体中 BEC 驱动的肝脏再生来确定 Bmp 信号传导在 BEC 驱动的肝脏再生中的作用。目标 3：我们将通过测试 Id2a 介导 Bmp 信号对 BEC 驱动的肝再生的影响的工作假设，确定 Id2a（转录因子分化家族抑制剂的成员）在 BEC 驱动的肝再生中的作用，已知 Id2a 是多种组织中 Bmp 信号传导的直接靶标。这项工作的完成将揭示 Bmp 信号调节 BEC 驱动的肝再生的机制，从而显着推进肝再生领域的发展。此外，他们还将为如何增强和完成慢性肝病患者的 BEC 驱动的肝再生作为治疗方法提供新的见解。