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.

肠道传染病是全球发病率和死亡率的重要原因，患有腹泻疾病 是年轻人死亡的主要原因之一。详细了解之间的相互作用 由于病原体在内部生长，肠病原体和人类宿主受到限制 宿主组织。工人通常使用动物感染和组织培养重建人类疾病事件 - 基于分析病原体宿主界面的模型。然而，人类疾病通常复制不佳 在动物模型中，虽然组织培养模型缺乏复杂的疾病期间完全重建事件的复杂性 引入一组复杂的宿主细胞。解决这些问题并提供更多与生理相关的问题 研究肠病发生的工人使用的模型，该应用提出了一个肠中的中心 工程组织中的疾病（CEDET）生成人类生物工程的三维模型 源自人类临床肠细胞的组织。 CEDET团队开发的工程组织将 直接挑战肠病原体，以制定更准确的分析策略 与已知的组织培养模型中的工作相比，人类宿主中发生的事件。 CEDET将塔夫茨大学工程和医疗校园的调查员与 胃肠病医生专注于确定分析肠病毒之间界面的新策略 和临床起源的肠细胞。拟议的CEDET将开发用于工程的组织平台 具有特定代谢需求的病原体，被描述为单独但协同项目。在项目中 1，工程组织将用于生成模型系统，其中顶面和基础面孔 上皮将暴露于不同的O2张力，以允许艰难梭菌的研究，严格的厌氧 生物。项目2将开发人类肠道粘膜的3D体外组织模型并研究 弧菌霍乱和肠病耶尔森氏菌属的人类上皮感染。这个项目将允许 开发可进行的3D人类肠道组织模型系统，用于研究特定机械 对于肠道病原体而言至关重要的步骤，成功地定居宿主肠。最后，在项目3中 3D肠模型将用于克服开发连续系统的技术障碍 加密环球的传播，原代人细胞中宿主 - 寄生虫相互作用的研究和系统 用于审查人类肠道结构的药物筛查。每个项目都是由建议的目标驱动的 构建具有增加复杂性的人造组织，引入免疫细胞，原代细胞来自 诊所中的内窥镜分离，以及O2控制环境中的人类微生物组样品。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。