The Role of Macrophages in Hepatobiliary Development

巨噬细胞在肝胆发育中的作用

• 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
• 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

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，参与营养物质的代谢和解毒。 内源性和外源性产物。为了管理与抗原和微生物的接触，肝脏 含有约 80% 的人体驻留巨噬细胞。巨噬细胞在肝脏中的作用 发展完全未知。在我们的初步工作中，我们证明遗传或 诱导的巨噬细胞损失严重影响肝胆发育，减少胆管树 分支并影响肝细胞极化。我们拟议工作的目标是雇用 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 用于肝脏发育。我们的中心假设是巨噬细胞被正在发育的细胞所吸引 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。两个具体 提出的目标是确定巨噬细胞在正常肝胆发育中的作用 发展。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。我们的 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。