The Role of Macrophages in Hepatobiliary Development

巨噬细胞在肝胆发育中的作用

基本信息

批准号：
10680846
负责人：
Wolfram Goessling
金额：
$ 61.6万
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：
2023-05-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680846
关键词：
Ablation Affect Alagille Syndrome Anatomy Antigens Architecture Area Bile fluid Biliary Biliary Atresia Cells Child Childhood Cues Defect Development Developmental Process Differentiation and Growth Disease Drug Metabolic Detoxication Embryo Embryonic Development Exhibits Exposure to Extrahepatic Fishes Genetic Goals Growth Health Hepatobiliary Hepatocyte Homeostasis Image Analysis Immune Immune response Immunity Impairment Inflammation Inflammation Mediators Inflammatory Inflammatory Response Kupffer Cells Liver Liver diseases Location Macrophage Mediating Metabolic Methods Microbe Microscopy Molecular Morphogenesis Natural regeneration Obstruction Organ Outcome Pathogenesis Play Population Production Reporter Reporter Genes Resolution Role Serum Proteins Shapes Signal Pathway Signal Transduction Source TNF gene Toxin Transforming Growth Factor beta Transgenic Mice Transgenic Organisms Work Yolk Sac Zebrafish bile duct biliary tract chemical genetics confocal imaging experimental study genetic approach hematopoietic stem cell formation in utero in vivo in vivo imaging innovation insight liver development liver function liver transplantation microbial products mutant notch protein novel nutrient metabolism quantitative imaging spatiotemporal wound healing

项目摘要

Project Summary - The role of macrophages in hepatobiliary development The liver is a vital metabolic organ, involved in nutrient metabolism and detoxification of endogenous and exogenous products. To manage exposure to antigens and microbes, the liver harbors ~80% of the body’s residential macrophages. The role of macrophages in liver development is completely unknown. In our preliminary work we demonstrate that genetic or induced loss of macrophages severely affects hepatobiliary development, reducing biliary tree branching and affecting hepatocyte polarization. The objective in our proposed work is to employ macrophage-deficient zebrafish and transgenic reporter strains combined with high-resolution confocal imaging and novel image analysis methods to determine the importance of macrophages for liver development. Our central hypothesis is that macrophages are attracted to the developing liver bud by a temporal and location-specific expression of TNFα, and that macrophages mediate their effect on hepatobiliary development through modulation of TGFβ signaling. Two Specific Aims are proposed to define the role of macrophages for normal hepatobiliary development development. In Specific Aim 1 we will identify the exact periods during development when macrophages interact with the liver, and how their loss affects normal development and function. Specific Aim2 will define the molecular signals by which macrophages are attracted to the developing liver, and how macrophage-derived TGFβ signaling affects liver development. Our proposed work will provide critical new mechanistic insight into the contribution of macrophages to normal hepatobiliary development, and further elucidate the pathogenesis of developmental biliary defects in childhood.

项目摘要 - 巨噬细胞在肝胆发育中的作用肝脏是重要的代谢器官，参与营养代谢和解毒。为了管理与抗原和微生物的接触，肝脏。拥有约 80% 的人体驻留巨噬细胞巨噬细胞在肝脏中的作用。在我们的初步工作中，我们证明遗传或发育是完全未知的。诱导的巨噬细胞损失严重影响肝胆发育，减少胆管树分支和影响肝细胞极化我们提出的工作的目标是采用。巨噬细胞缺陷斑马鱼和转基因报告菌株与高分辨率相结合共焦成像和新颖的图像分析方法确定巨噬细胞的重要性我们的中心假设是巨噬细胞被发育中的细胞所吸引。肝芽通过 TNFα 的时间和位置特异性表达而发挥作用，巨噬细胞介导它们通过调节 TGFβ 信号传导对肝胆发育产生影响。提出的目标是确定巨噬细胞在正常肝胆发育中的作用在具体目标 1 中，我们将确定开发过程中的确切时期。巨噬细胞与肝脏相互作用，以及它们的损失如何影响正常发育和功能。具体目标2将定义巨噬细胞被吸引到的分子信号肝脏发育，以及巨噬细胞衍生的 TGFβ 信号如何影响肝脏发育。拟议的工作将为巨噬细胞的贡献提供重要的新机制见解影响肝胆正常发育，进一步阐明发育的发病机制儿童期胆道缺陷。