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，它们在调节组织发育和维持组织稳态方面起着关键作用。这些细胞也是先天免疫系统的重要组成部分，它们通过吞噬和破坏病原体，为抵御感染提供了重要的第一道防线。然而，在某些情况下，这些重要巨噬细胞功能的失调可导致一系列炎症性疾病。巨噬细胞在整个身体中占据许多不同的生态位，并可能根据这些位置发挥不同的作用，例如提供体内平衡支持或对体表的免疫监视。这些高度变化的特征和功能是如何在巨噬细胞或它们的前体细胞中留下印记的，目前尚不清楚。同样，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）中复制也不确定。然而，已经确定了一系列巨噬细胞亚群分化所需的基因。例如，核受体LXRa对于脾脏边缘区巨噬细胞的发育至关重要。贝恩博士实验室的研究表明，转录因子EGR2在肺肺泡巨噬细胞的分化中发挥了重要作用。CSF1R基因中高度保守的超级增强子FIRE对特定组织中巨噬细胞的发育非常重要，包括胚胎、大脑（小胶质细胞）、皮肤（朗格汉斯细胞）、肾脏、心脏和腹腔。这个学生将比较来自一系列粘膜组织的单核细胞和巨噬细胞的转录组。然后，这些数据将用于识别跨组织的单核细胞和巨噬细胞共享的共同核心特征，以及限制于来自特定生态位的细胞、具有特定功能的细胞或来自不同病理疾病（稳态、免疫监视、炎症等）的细胞的基因亚群。从这些研究中鉴定出的关键基因的表达将在组织中使用一系列细胞和生物成像方法进行验证。在数据集或材料可用的情况下，学生还将确定在本项目中鉴定的细胞转录组是否在物种中保守。从本项目的研究中发现单核细胞/巨噬细胞功能的新调节因子可能有助于开发新的疗法来改善先天免疫系统的免疫监视或治疗某些发育性或炎症性疾病。

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.