Center for Enteric Diseases in Engineered Tissues

工程组织肠道疾病中心

• 批准号: 9312409
• 负责人: Ralph R. Isberg
• 金额: $ 165.67万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-07 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312409
• 关键词: 3-Dimensional; Address; Anaerobic Bacteria; Animal Model; Animals; Anti-Infective Agents; Apical; Bacteria; Biochemical; Biological Assay; Biological Models; Biomedical Engineering; Boston; Cause of Death; Cell Communication; Cells; Clinic; Clinical; Clostridium difficile; Collaborations; Communicable Diseases; Communication; Communities; Complex; Controlled Environment; Cryptococcus; Cryptosporidium; Cryptosporidium parvum; Data; Development; Dimensions; Disease; Engineering; Ensure; Enteral; Environment; Epithelium; Event; Face; Gastroenterologist; Gastroenterology; Gene Expression; Genetic; Goals; Human; Human Microbiome; Hypoxia; Immune; In Vitro; Individual; Infection; Integration Host Factors; Intestines; Investigation; Medical; Medical center; Metabolic; Methods; Microbe; Microbial Physiology; Modeling; Morbidity - disease rate; Mucous Membrane; Organ; Organism; Outcome; Oxygen; Parasites; Pathogenesis; Pathogenicity; Patients; Physiological; Preclinical Drug Evaluation; Process; Property; Research; Research Personnel; Sampling; Site; Specialist; Structure; System; Therapeutic; Tissue Engineering; Tissue Model; Tissues; Universities; Vibrio cholerae; Vision; Work; Yersinia; antimicrobial; antimicrobial drug; assay development; base; clinical material; cohort; design; enteric pathogen; experimental analysis; human disease; human tissue; improved; in vitro Model; innovation; interest; member; microbial host; microbiota; microorganism; microorganism interaction; mortality; novel; novel strategies; pathogen; programs; screening; symposium; synergism; three-dimensional modeling; tissue culture; tissue support frame

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.

肠道传染病是全世界发病和死亡的重要原因，其中腹泻病 是年轻人死亡的主要原因之一。详细了解之间的相互作用 由于病原体在体内生长时难以接近，肠道病原体和人类宿主受到限制 宿主组织。工作人员通常利用动物感染和组织培养来重建人类疾病事件—— 基于模型来分析病原体-宿主界面。然而，人类疾病往往难以复制 在动物模型中，而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生理相关的 供研究肠道发病机制的工作者使用的模型，该应用程序提出了一个肠道中心 工程组织疾病 (CEDET) 用于生成人体生物工程三维模型 源自人类临床肠道细胞的组织。 CEDET团队开发的工程组织将 直接接受肠道病原体的挑战，以寻求开发更准确的分析策略 与已知组织培养模型中的工作相比，模拟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 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。项目中 1、工程组织将用于生成模型系统，其中组织的顶面和基面 上皮细胞将暴露在不同的氧气张力下，以便研究艰难梭菌（一种严格的厌氧菌） 生物。项目2将开发人体肠粘膜3D体外组织模型并进行研究 霍乱弧菌和肠道致病性耶尔森氏菌对人类上皮细胞的感染。该项目将允许 开发易于处理的 3D 人体肠道组织模型系统，用于研究具体机制 对于肠道病原体成功定植宿主肠道非常重要的步骤。最后，在项目3中， 3D肠道模型将用于克服开发连续性系统的技术障碍 隐球菌的繁殖，原代人类细胞和系统中宿主与寄生虫相互作用的研究 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，这些目标旨在 构建越来越复杂的人造组织，引入免疫细胞，来自于的原代细胞 临床中的内窥镜分离，以及 O2 控制环境中的人类微生物组样本。整个 中心将由行政和科学核心驱动，其明确目的是支持 各个项目之间的协同作用。