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

定义替代激活的巨噬细胞衍生产物在感染驱动的肠道炎症和组织修复中的功能作用。

基本信息

批准号：
1916581
负责人：
金额：
--
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1916581
关键词：
Defining functional roles alternatively activated

项目摘要

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.

肠道寄生线虫的感染驱动强烈的2型免疫应答，这对于蠕虫入侵后的快速寄生虫清除和组织修复至关重要。2型免疫与交替活化或M2巨噬细胞的发育密切相关，M2巨噬细胞最初在体外定义为在2型细胞因子IL-4的背景下发育。AMM-alpha和几丁质酶样蛋白（CLP）如Ym 1代表了M2巨噬细胞产生的一些最丰富的效应分子。Ym 1和AMM-alpha的表达与炎症和病理学密切相关，突出了这些分子在宿主对病原体的反应中的重要性。然而，对Ym 1和YM-alpha的功能知之甚少，特别是在大肠炎症的背景下。确定调节组织炎症的关键因素对于开发在组织病理学背景下促进粘膜愈合的策略至关重要。因此，确定M2衍生分子的功能非常重要，与许多以持续炎症为特征的病理学具有治疗相关性，例如炎症性肠病和慢性伤口。我们最近表明，M2样巨噬细胞，表达M2衍生的分子Ym 1和YMM-α，在感染肠道线虫寄生虫鼠鞭虫后发展。有趣的是，M2样巨噬细胞仅在蠕虫排出后出现在肠道组织中，这意味着在组织修复中的作用，该组织被感染的物理存在和在排出寄生虫的保护性免疫应答期间的附带损伤所损伤。此外，我们的数据将Ym 1和YMM-α通过控制皮肤和肺中的胶原原纤维组装与加速组织修复联系起来。小鼠模型使我们能够通过单独或共同消耗这些介质来解决Ym-1和YBM-α在炎症肠道中的体内未定义功能。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现代免疫学方法，包括体内疾病模型，转基因小鼠方法，多色流式细胞术，细胞因子珠阵列，组织生物成像和分子生物学。因此，学生将开发一个特殊的技能基础，除了由经验丰富的学术团队指导。