Center for Enteric Diseases in Engineered Tissues

肠道传染病是世界范围内发病和死亡的重要原因， 是导致年轻人死亡的主要原因之一。详细了解 肠道病原体和人类宿主之间的相互作用是有限的，这是由于病原体在肠道内生长时无法接近。 宿主组织工作人员通常使用动物感染和组织培养来重建人类疾病事件- 的模型来分析病原体-宿主界面。然而，人类疾病的复制能力往往很差， 在动物模型中，虽然组织培养模型缺乏完全重建疾病期间事件的复杂性， 引入一组复杂的宿主细胞。为了解决这些问题，并提供更多的生理相关的 模型使用的工人研究肠道发病机制，本申请提出了一个中心的肠道 工程组织中的疾病（CEDET），以生成人体的生物工程三维模型 来源于人类临床肠细胞的组织。CEDET团队开发的工程组织将 直接挑战肠道病原体，以寻求开发更准确的分析策略， 与在已知的组织培养模型中的工作相比，模拟在人类宿主中发生的事件。 CEDET汇集了来自塔夫茨大学工程和医学校区的研究人员， 一位胃肠病学家，专注于确定分析肠道病原体之间界面的新策略 和临床来源的肠细胞。拟议的CEDET将开发工程组织平台， 具有特定代谢要求的病原体，被描述为单独但协同的项目。在项目 1，工程化组织将用于产生模型系统，其中， 上皮将暴露于不同的O2张力，以允许艰难梭菌，严格厌氧的研究 有机体项目2将开发人体肠图尼卡粘膜的三维体外组织模型，并研究 霍乱弧菌和肠致病性耶尔森氏菌感染人体上皮细胞该项目将使 开发了一个易于处理的三维人体肠道组织模型系统，用于研究特定的机制， 这些步骤对于肠道病原体成功地定殖宿主肠道是重要的。最后，在项目3中， 3D肠道模型将用于克服开发一个系统的技术障碍， 隐球菌的繁殖，原代人类细胞中宿主-寄生虫相互作用的研究和系统 用于药物筛选重现人类肠道结构。每一个项目都是由目标驱动的，这些目标建议： 构建越来越复杂的人工组织，引入免疫细胞，来自 临床中的内窥镜隔离，以及O2控制环境中的人体微生物组样本。整个 中心将由行政和科学核心推动，其明确目的是支持 个别项目之间的协同作用。

Enteric infectious diseases are important causes of morbidity and mortality worldwide, with diarrheal diseases being among the leading causes of death in the young. Detailed understanding of the interaction between enteropathogens and the human host is limited due to the inaccessibility of pathogens while growing within host tissues. Workers generally reconstruct human disease events using animal infection and tissue culture- based models to analyze the pathogen-host interface. Human diseases, however, are often poorly reproduced in animal models, while tissue culture models lack the complexity to fully reconstruct events during disease that bring in a complex group of host cells. To address these issues and provide more physiologically relevant models for use by workers studying enteropathogenesis, this application proposes a Center on Enteric Diseases in Engineered Tissues (CEDET) to generate bioengineered three-dimensional models of human tissue derived from human clinical intestinal cells. The engineered tissues developed by the CEDET team will be challenged directly with enteropathogens in a quest to develop analytic strategies that more accurately mimic events that occur in the human host compared to work in known tissue culture models. The CEDET brings investigators from the Engineering and Medical campuses of Tufts University together with a gastroenterologist to focus on identifying new strategies for analyzing the interface between enteropathogens and intestinal cells of clinical origin. The proposed CEDET will develop engineered tissue platforms for pathogens having specific metabolic requirements, described as individual but synergizing projects. In Project 1, the engineered tissues will be used to generate a model system in which the apical and basal faces of the epithelium will be exposed to different O2 tensions, to allow the study of Clostridium difficile, a strict anaerobic organism. Project 2 will develop a 3D in vitro tissue model of the human intestine tunica mucosa and study infections of human epithelium by Vibrio cholera and enteropathogenic Yersinia spp. This Project will allow the development of a tractable 3D human intestinal tissue model system for studying the specific mechanistic steps that are important for enteric pathogens to successfully colonize the host intestine. Finally, in Project 3, the 3D intestinal models will be used to overcome the technical hurdle of developing a system for continuous propagation of Cryptococcus, investigation of host-parasite interactions in primary human cells and a system for drug screening recapitulating human gut structure. Each of the Projects is driven by Aims that propose to construct artificial tissues of increasing complexity, bringing in immune cells, primary cells derived from endoscopic isolation in the clinic, and human microbiome samples in O2-controlled environments. The entire Center will be driven by Administrative and Scientific Cores, which have the express purpose of supporting synergy between the individual Projects.