Determining Monocyte and Macrophage Diversity in the Mucosal Immune System

巨噬细胞是人体大多数健康组织中最丰富的免疫细胞类型之一，在调节组织发育和维持组织动态平衡方面发挥着关键作用。这些细胞也是先天免疫系统的重要组成部分，它们通过吞噬和摧毁病原体，为抵御感染提供了重要的第一道防线。然而，在某些情况下，这些重要的巨噬细胞功能的失调可能会导致一系列炎症性疾病。巨噬细胞在体内占据着许多不同的位置，并可能根据这些位置传递不同的角色，如提供体内平衡支持或对身体表面的免疫监视。这些高度不同的特征和功能是如何印记在巨噬细胞或其前体细胞中的，目前还知之甚少。同样，还不确定在一个组织位置(如肺)的特定巨噬细胞亚型是否也在其他粘膜组织(如肠、鼻腔等)中复制。然而，已经确定了某些巨噬细胞亚群分化所需的一系列基因。例如，核受体LXRa对于脾边缘区巨噬细胞的发育是必不可少的。贝恩博士实验室的研究表明，转录因子EGR2如何在肺内肺泡巨噬细胞的分化中发挥重要作用。CSF1R基因中高度保守的超增强子FIRE对特定组织中巨噬细胞的发育非常重要，包括胚胎、脑(小胶质细胞)、皮肤(朗格汉斯细胞)、肾脏、心脏和腹膜腔。本文将比较一系列粘膜组织中单核细胞和巨噬细胞的转录。然后，这些数据将被用来识别组织中单核细胞和巨噬细胞共有的共同核心特征，以及局限于来自特定生态位细胞、具有特定功能的细胞或来自不同病理疾病(动态平衡、免疫监测、炎症等)的细胞的基因亚集。然后，将使用一系列细胞和生物成像方法在组织中验证从这些研究中确定的关键基因的表达。在有数据集或材料的情况下，学生还将确定本项目中确定的细胞转录本是否在物种之间保守。从本项目中的研究中识别单核/巨噬细胞功能的新调节因素可能有助于开发新的疗法，以改善先天性免疫系统的免疫监控，或治疗某些发育或炎症性疾病。

Macrophages are amongst the most abundance immune cell type in most healthy tissues of the body where they play key roles in regulating tissue development and maintaining tissue homeostasis. These cells are also an essential component of the innate immune system where they provide an important first line of defence against infection by phagocytosing and destroying pathogens. However, in some circumstances the dysregulation of these important macrophage function can contribute to a range of inflammatory diseases. Macrophages occupy many varied niches throughout the body and may convey distinct roles depending on these locations, such as provision of homeostatic support or immunosurveillance of body surfaces. How these highly varied characteristics and functions are imprinted in the macrophages or their precursor cells is poorly understood. Similarly, it is uncertain whether specific macrophage sub-types in one tissue location such as the lung, are also replicated in other mucosal tissues such as the intestine, nasal cavity etc. However, a range of genes have been identified that are required for the differentiation of certain macrophage subsets. For example, the nuclear receptor LXRa is essential for the development of macrophages in the marginal zone of the spleen. Studies from Dr. Bain's lab have shown how the transcription factor EGR2 plays an important role in the differentiation of alveolar macrophages in the lung. The highly conserved super-enhancer, FIRE, within the CSF1R gene is important for the development of macrophages in specific tissues including the embryo, the brain (microglia), the skin (Langerhans cells), kidney, heart and peritoneal cavity.This studentship will compare the transcriptomes of monocytes and macrophages from a range of mucosal tissues. These data will then be used to identify common core signatures shared in monocytes and macrophages across tissues, as well as subsets of genes restricted to cells derived from specific niches, cells with specific functions or those from different pathological diseases (homeostasis, immunosurveillance, inflammation etc.). The expression of key genes identified from these studies will then be validated in tissues using a range of cellular and bio-imaging approaches. Where data sets or materials are available the student will also determine whether the cell transcriptomes identified in this project are conserved across species.The identification of novel regulators of monocyte/macrophage function from the studies in this project may aid the development of novel therapies to improve immunosurveillance by the innate immune system or treat certain developmental or inflammatory diseases.