The role of liver progenitor cells in liver regeneration

肝祖细胞在肝再生中的作用

基本信息

批准号：
10607301
负责人：
Wolfram Goessling
金额：
$ 66.91万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607301
关键词：
Ablation Acetaminophen Acute Adult Affect Atlases Bile fluid Biliary Blood COVID-19 pandemic Cells Cessation of life Chemicals Chronic Data Set Dedications Development Endoderm Cell Epidermal Growth Factor Receptor Epithelial Cell Proliferation Epithelial Cells Equipment and supply inventories Experimental Autoimmune Encephalomyelitis FRAP1 gene Fibrosis Fishes Gallbladder Gene Expression Generations Genetic Genetic Transcription Goals Hepatic Hepatocyte Homeostasis Human Inflammation Injury Intestines Liver Liver Failure Liver Regeneration Liver Stem Cell Maps Mediating Metabolic Methods Microscopy Modeling Molecular Morbidity - disease rate Morphology Mus Muscle Natural regeneration Organ Outcome PIK3CG gene Partial Hepatectomy Pathway interactions Patients Phenotype Population Process Proliferating Rattus Regenerative capacity Regenerative response Reporter Resolution Role Signal Pathway Signal Transduction Skin Therapeutic Therapeutic Intervention Tissues Work Zebrafish adult stem cell airway epithelium cell type chronic liver disease experimental study hepatocyte injury high resolution imaging insight liver development liver function liver injury liver repair mTOR Signaling Pathway mortality novel organ growth organ regeneration oval cell progenitor regenerative response to injury self-renewal single-cell RNA sequencing stem cell population stem cells timeline tool transcription factor transcriptomics

Ablation Acetaminophen Acute Adult Affect Atlases Bile fluid Biliary Blood COVID-19 pandemic Cells Cessation of life Chemicals Chronic Data Set Dedications Development Endoderm Cell Epidermal Growth Factor Receptor Epithelial Cell Proliferation Epithelial Cells Equipment and supply inventories Experimental Autoimmune Encephalomyelitis FRAP1 gene Fibrosis Fishes Gallbladder Gene Expression Generations Genetic Genetic Transcription Goals Hepatic Hepatocyte Homeostasis Human Inflammation Injury Intestines Liver Liver Failure Liver Regeneration Liver Stem Cell Maps Mediating Metabolic Methods Microscopy Modeling Molecular Morbidity - disease rate Morphology Mus Muscle Natural regeneration Organ Outcome PIK3CG gene Partial Hepatectomy Pathway interactions Patients Phenotype Population Process Proliferating Rattus Regenerative capacity Regenerative response Reporter Resolution Role Signal Pathway Signal Transduction Skin Therapeutic Therapeutic Intervention Tissues Work Zebrafish adult stem cell airway epithelium cell type chronic liver disease experimental study hepatocyte injury high resolution imaging insight liver development liver function liver injury liver repair mTOR Signaling Pathway mortality novel organ growth organ regeneration oval cell progenitor regenerative response to injury self-renewal single-cell RNA sequencing stem cell population stem cells timeline tool transcription factor transcriptomics

展开

项目摘要

Project Summary - The role of liver progenitor cells in liver regeneration Acute and chronic liver disease causes liver failure and is a growing cause for morbidity and mortality. The COVID-19 pandemic has further increased the magnitude of this problem. The liver is a highly regenerative organ, yet the presence of a dedicated stem cell population remains controversial. In our preliminary work, we describe a near-total hepatocyte ablation model in zebrafish where organ regeneration is derived from biliary epithelial cells. Our objective here is to characterize the functional implications and molecular mechanisms of EAE to affect organ development. Our central hypothesis is that severe hepatocyte injury will reveal the facultative stem cell potential of biliary epithelial cells. This process appears to be driven by EGFR, PI3K, and mTOR signaling. Two Specific Aims are proposed to define the generation and contribution of facultative hepatic stem cells. In Specific Aim 1 we will utilize single-cell transcriptomic and high-resolution imaging analyses after near-total hepatocyte ablation to investigate whether and when biliary epithelial cells undergo transcriptional and morphological changes to become hepatocytes. In the process, we will generate an inventory of all liver cells in the zebrafish and determine evolutionary conservation of cell identity and function by comparison to murine and human liver datasets. Specific Aim2 will determine the degree of biliary epithelial cell proliferation hepatoblast transcription factors gene expression prior to hepatocyte differentiation and define the signaling pathways involved in the generation, function and proliferation of this facultative stem cell population. Identification of a signal like EGFR that can cause biliary epithelial cells to become hepatocytes has significant therapeutic potential for patients with liver failure.

项目摘要 - 肝祖细胞在肝脏再生中的作用急性和慢性肝病会导致肝衰竭，并且是发病率和死亡。 COVID-19大流行进一步增加了该问题的幅度。肝脏是高度再生器官，但仍存在专用的干细胞种群有争议的。在我们的初步工作中，我们描述了一种近乎全部的肝细胞消融模型斑马鱼，其中器官再生源自胆道上皮细胞。我们的目标是表征EAE的功能含义和分子机制影响器官发展。我们的中心假设是严重的肝细胞损伤将揭示兼职胆道上皮细胞的干细胞电位。此过程似乎是由EGFR驱动的，PI3K，和mTOR信号传导。提出了两个具体目标来定义生成和贡献辅助肝干细胞。在特定目标1中，我们将使用单细胞转录组和几乎全肝细胞消融后进行高分辨率成像分析，以研究是否和当胆道上皮细胞经历转录和形态学变化肝细胞。在此过程中，我们将生成斑马鱼中所有肝细胞的清单通过与鼠相比，确定细胞身份和功能的进化保护人肝数据集。特定的AIM2将确定胆道上皮细胞增殖的程度肝细胞分化之前的肝类母细胞转录因子基因表达并定义该夫妇的发电，功能和增殖涉及的信号传导途径干细胞种群。识别像EGFR这样的信号，该信号可能导致胆汁上皮细胞成为肝细胞对于肝衰竭患者具有显着的治疗潜力。