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 - 巨噬细胞在肝胆管发育中的作用肝脏是重要的代谢器官，参与营养代谢和排毒内源性和外源产品。为了管理暴露于抗原和微生物，肝脏港口约有80％的人体居民巨噬细胞。巨噬细胞在肝脏中的作用发展是完全未知的。在我们的初步工作中，我们证明了遗传或诱导的巨噬细胞的丧失严重影响肝胆管发育，减少了胆道分支和影响肝细胞极化。我们拟议的工作的目的是雇用缺乏巨噬细胞的斑马鱼和转基因记者菌株与高分辨率结合共聚焦成像和新型图像分析方法来确定巨噬细胞的重要性用于肝脏发育。我们的中心假设是巨噬细胞被发展肝芽通过TNFα的临时和特定位置表达，巨噬细胞介导通过调节TGFβ信号传导，它们对肝胆管发育的影响。两个具体提出了目的来定义巨噬细胞在正常肝胆管发育中的作用发展。在特定目标1中，我们将确定开发过程中的确切周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的发育和功能。特定的AIM2将定义巨噬细胞被吸引到的分子信号发展肝脏，以及巨噬细胞衍生的TGFβ信号如何影响肝发育。我们的拟议的工作将为巨噬细胞的贡献提供关键的新机械洞察力正常的肝胆发育，并进一步阐明发育的发病机理童年时期的胆道缺陷。