Defining functional roles of alternatively activated macrophage-derived products in infection-driven intestinal inflammation and tissue repair.

寄生在肠道内的线虫感染驱动强烈的2型免疫反应，这对于寄生虫入侵后的快速清除和组织修复非常重要。2型免疫与交替活化或M2巨噬细胞的发育密切相关，最初在体外被定义为在2型细胞因子IL-4的背景下发育。relm - α和几丁质酶样蛋白（CLPs）如Ym1代表了M2巨噬细胞产生的一些最丰富的效应分子。Ym1和relm - α的表达与炎症和病理密切相关，突出了这些分子在宿主对病原体反应中的重要性。然而，人们对Ym1和relm - α的功能知之甚少，特别是在大肠炎症的情况下。确定调节组织炎症的关键因素对于在组织病理学背景下制定促进粘膜愈合的策略至关重要。因此，确定m2衍生分子的功能是重要的，与许多以持续炎症为特征的病理（如炎症性肠病和慢性伤口）的治疗相关。我们最近的研究表明，表达m2衍生分子Ym1和relm - α的m2样巨噬细胞在感染肠道线虫虫Trichuris muris后发育。有趣的是，m2样巨噬细胞仅在蠕虫驱逐后出现在肠道组织中，这意味着在组织修复中起作用，这些组织受到感染的物理存在和驱逐寄生虫的保护性免疫反应期间的附带损伤。此外，我们的数据将Ym1和RELM-alpha通过控制皮肤和肺中的胶原原纤维组装来加速组织修复。小鼠模型中m2样巨噬细胞的精确和可预测的出现使我们能够通过单独或集体消耗这些介质来解决炎症肠道中m-1和relm - α在体内的未定义功能。我们将使用基因靶向小鼠的组合来实现这一目标，包括产生一种新的转基因，以及感染后的体内抗体治疗，以确定在缺乏这些介质的情况下组织修复过程中的任何缺陷。该项目将利用一系列当代免疫学方法，包括体内疾病模型、转基因小鼠方法、多色流式细胞术、细胞因子头阵列、组织生物成像和分子生物学。因此，除了由经验丰富的学术团队指导外，学生还将发展出卓越的技能基础。

Infections with gut-dwelling parasitic nematodes drive strong type 2 immune responses that are important for rapid parasite clearance and tissue repair following worm invasion. Type 2 immunity associates closely with the development of alternatively activated, or M2 macrophages, originally defined in vitro as developing in the context of the type 2 cytokine IL-4. RELM-alpha and chitinase-like proteins (CLPs) like Ym1 represent some of the most abundant effector molecules produced by M2 macrophages. Expression of Ym1 and RELM-alpha, correlate strongly with inflammation and pathology, highlighting the importance of these molecules in host responses to pathogens. However, there is remarkably little known about the functions of Ym1 and RELM-alpha, particularly in the context of large intestinal inflammation. Defining key factors that regulate tissue inflammation will be critical for developing strategies that promote mucosal healing in the context of tissue pathology.Thus, defining the function(s) of M2-derived molecules is important, with therapeutic relevance to many pathologies that feature persisting inflammation, such as inflammatory bowel disease and chronic wounds.We have recently shown that M2-like macrophages, expressing the M2-derived molecules Ym1 and RELM-alpha, develop post infection with the intestinal nematode parasite Trichuris muris. Interestingly, the M2-like macrophages only emerge in gut tissue after worm expulsion, implying a role in the repair of tissue, damaged by both the physical presence of the infection and by collateral damage during the protective immune response which expels the parasite. Additionally, our data links both Ym1 and RELM-alpha to accelerated tissue repair through the control of collagen fibril assembly in the skin and lung.The precise and predictable emergence of the M2-like macrophage in the T. muris mouse model allows us to address the undefined functions of Ym-1and RELM-alpha in vivo in the inflamed intestine, by depleting these mediators individually or collectively. We will achieve this using a combination of gene targeted mice, including the generation of a novel transgenic, and in vivo antibody treatment post infection, to identify any defects in the tissue reparative process in the absence of these mediators.The project will utilise a range of contemporary methodologies in immunology, including in vivo models of disease, transgenic mouse methodologies, multi-colour flow cytometry, cytokine bead arrays, tissue bioimaging and molecular biology. As such the student will develop an exceptional skills base, in addition to being mentored by a highly experienced academic team.