The Role of Macrophages in Hepatobiliary Development

项目摘要-巨噬细胞在肝胆发育中的作用 肝脏是一个重要的代谢器官，参与营养代谢和解毒。 内源性和外源性产品。为了控制暴露于抗原和微生物，肝脏 容纳了体内80%的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，我们证明了基因或 巨噬细胞的诱导损失严重影响肝胆发育，减少胆道系统 分支并影响肝细胞极化。我们的工作目标是雇用 巨噬细胞缺陷斑马鱼和转基因报告菌株结合高分辨率 共聚焦成像和新的图像分析方法来确定巨噬细胞的重要性 促进肝脏发育我们的中心假设是巨噬细胞被吸引到发育中的 肝芽由TNFα时间和位置特异性表达，巨噬细胞介导 它们通过调节TGFβ信号传导对肝胆发育的影响。两个具体 目的是确定正常肝胆发育的巨噬细胞的作用 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。 特异性Aim 2将定义巨噬细胞被吸引到细胞的分子信号。 肝脏发育，以及巨噬细胞来源的TGFβ信号传导如何影响肝脏发育。我们 拟议的工作将提供关键的新机制的见解巨噬细胞的贡献， 正常肝胆发育，进一步阐明发育性黄疸的发病机制 儿童时期的胆道缺陷。

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.