Center for Enteric Diseases in Engineered Tissues

肠道传染病是世界范围内发病率和死亡率的重要原因，腹泻疾病也是如此。 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是有限的，因为病原体在体内生长时无法接触到 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- 基于模型分析病原体-宿主界面。然而，人类疾病的重复性往往很差。 在动物模型中，尽管组织培养模型缺乏完全重建疾病期间事件的复杂性，但 引入一组复杂的宿主细胞。以解决这些问题，并提供更多与生理相关的 供研究肠道病变的工作人员使用的模型，该应用程序提出了一个肠道中心 工程组织中的疾病(CEDET)以生成人体的生物工程三维模型 来源于人类临床肠道细胞的组织。由CEDET团队开发的工程组织将 直接面对肠道病原体的挑战，以寻求开发更准确的分析策略 与已知的组织培养模型相比，模拟在人类宿主中发生的事件。 CEDET将来自塔夫茨大学工程和医学校区的研究人员与 胃肠病学家将专注于确定分析肠道病原体之间的界面的新策略 和临床来源的肠道细胞。拟议的CEDET将开发工程组织平台，用于 具有特定代谢要求的病原体，被描述为单独但协同的项目。在项目中 1，工程组织将被用于生成模型系统，在该模型系统中， 上皮细胞将暴露在不同的氧气压力下，以允许研究艰难梭菌，一种严格的厌氧 有机体。项目2将开发人体肠黏膜的3D体外组织模型，并进行研究 霍乱弧菌和肠源性耶尔森氏菌对人上皮细胞的感染该项目将允许 用于研究肠道特殊机制的易操作的三维人体肠道组织模型系统的研制 肠道病原体成功定植宿主肠道的重要步骤。最后，在项目3中， 3D肠道模型将被用来克服开发连续的 隐球菌的繁殖、原代人体细胞内宿主与寄生虫相互作用的研究及系统 用于药物筛选，重现人体肠道结构。每个项目都是由目标驱动的，这些目标提出 构建日益复杂的人造组织，引入免疫细胞，来自 临床中的内窥镜分离，以及氧气控制环境中的人体微生物样本。整个 中心将由行政和科学核心驱动，这两个核心具有明确的支持目的 各个项目之间的协同效应。

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.