Elucidating the role of Id2a in liver development and regeneration

阐明 Id2a 在肝脏发育和再生中的作用

• 批准号: 8908218
• 负责人: Mehwish Khaliq
• 金额: $ 4.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8908218
• 关键词: Ablation; Address; Adopted; Alternative Therapies; Animal Model; Appearance; Biliary; Cause of Death; Cell Proliferation; Cells; Cessation of life; Cirrhosis; Data; Defect; Development; Developmental Process; Diagnosis; Differentiation Inhibitor; Epithelial Cells; Event; Fertilization; Genetic; Goals; Health Care Costs; Heat-Shock Response; Hepatic; Hepatic Mass; Hepatic Tissue; Hepatocyte; Hour; Inhibitor of Differentiation Proteins; Injury; Laboratories; Larva; Lead; Liver; Liver Cirrhosis; Liver Failure; Liver Regeneration; Liver diseases; Mediating; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Natural regeneration; Nodule; Outcome; Palliative Care; Patients; Phenotype; Portal Hypertension; Process; Proliferating; Quality of life; Reagent; Recovery of Function; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Severity of illness; Signal Pathway; Signal Transduction; Staging; Structure; Symptoms; Time; Tissues; Transgenic Organisms; United States; Up-Regulation; Work; Zebrafish; chronic liver disease; cost; effective therapy; gain of function; helix-loop-helix protein differentiation inhibitor; improved; insight; liver cell proliferation; liver injury; liver transplantation; mortality; mutant; novel; overexpression; public health relevance; regenerative; restoration; tool; transcriptome sequencing

 DESCRIPTION (provided by applicant): Chronic liver disease encompasses the steady destruction of hepatic tissue over time, resulting in the replacement of healthy liver tissue with damaged fibrotic and cirrhotic tissue. Among other symptoms, cirrhosis manifests itself with regenerative hepatic nodules and portal hypertension, triggering a loss of liver functionality and poor quality of life. Moreover, in the United States, cirrhosis remains the 12th leading cause of death, incurring healthcare costs of billions of dollars in the process. Despite these astronomical costs and limited palliative care, the only effective treatment for cirrhosis is liver transplantaton. The demand for liver transplants however, far exceeds the availability of donor livers, underpinning the need for harnessing the liver's innate regenerative capacity. With that regard, we aim to understand the complete process of biliary epithelial cell (BEC)-driven liver regeneration: when hepatocyte proliferation is compromised following severe liver injury, BECs proliferate and contribute to the regenerating hepatocytes. Our lab has previously characterized the zebrafish model of BEC-driven liver regeneration, in which the BECs de-differentiate into hepatoblast-like cells (HB-LCs), proliferate and then re-differentiate into hepatocytes. Specifically, during this regenerative process, we found upregulation of the inhibitor of differentiation protein, Id2a. Using zebrafish as a model organism, the purpose of this proposal is to elucidate the role of Id2a in BEC-driven liver regeneration and liver development, since events involved in liver regeneration can also be implicated in liver development. We will utilize both loss- and gain-of-function approaches, including knockdown via antisense morpholino oligos (MOs), id2a mutants and an id2a overexpression heat-shock inducible line, Tg(hsp70: mCherry-T2A-id2a). These tools along with previously generated reagents in our lab will be instrumental in exposing the process by which the liver develops, sustains injury and subsequently regenerates to restore lost liver mass. Understanding these distinctive yet connected mechanisms will provide us with new insights to improve innate liver regeneration and develop novel therapies to treat chronic liver diseases.

 描述（由申请人提供）：慢性肝病包括肝组织随时间的持续破坏，导致健康肝组织被受损的纤维化和坏死组织替代。在其他症状中，肝硬化表现为再生性肝结节和门静脉高压，引发肝脏功能丧失和生活质量低下。此外，在美国，肝硬化仍然是第12大死亡原因，在此过程中产生数十亿美元的医疗费用。尽管这些天文数字 由于成本和有限的姑息治疗，肝硬化的唯一有效治疗方法是肝移植。然而，对肝脏移植的需求远远超过了供体肝脏的可用性，这支持了利用肝脏先天再生能力的需求。在这方面，我们的目标是了解胆管上皮细胞（BEC）驱动的肝再生的完整过程：当严重肝损伤后肝细胞增殖受到损害时，BEC增殖并有助于肝细胞再生。我们的实验室先前已经表征了BEC驱动的肝再生的斑马鱼模型，其中BEC去分化为成肝细胞样细胞（HB-LC），增殖然后再分化为肝细胞。具体来说，在这个再生过程中，我们发现分化蛋白Id 2a的抑制剂上调。使用斑马鱼作为模式生物，该提议的目的是阐明Id 2a在BEC驱动的肝再生和肝发育中的作用，因为涉及肝再生的事件也可能涉及肝发育。我们将利用功能丧失和功能获得两种方法，包括通过反义吗啉代寡核苷酸（MO）、id 2a突变体和id 2a过表达热休克诱导系Tg（hsp 70：mCherry-T2 A-id 2a）进行敲减。这些工具沿着我们实验室先前生成的试剂将有助于揭示肝脏发育、持续损伤和随后再生以恢复丢失的肝脏质量的过程。了解这些独特而又相互关联的机制将为我们提供新的见解，以改善先天性肝再生并开发治疗慢性肝病的新疗法。