Engineered human intestinal organoids: a modular system to model enteric disease

工程人体肠道类器官：模拟肠道疾病的模块化系统

• 批准号: 9240575
• 负责人: Jason Spence
• 金额: $ 133.52万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240575
• 关键词: Address; Affect; Animal Model; Antibiotic Resistance; Antigens; Appearance; Attention; Biological; Biological Models; Biology; Biomedical Engineering; Cell Culture Techniques; Cells; Cellular Immunity; Communicable Diseases; Complement; Complex; Crohn' s disease; Cues; Development; Disease; Elements; Engineering; Enteral; Environment; Epithelial; Epithelial Cells; Epithelium; Fluids and Secretions; Gastrointestinal tract structure; Goals; Health; Human; Human Engineering; Immune; Immune system; Immunology; In Vitro; Indigenous; Infection; Intestines; Lateral; Longitudinal Studies; Mechanics; Methods; Microbe; Microfluidics; Modality; Modeling; Monitor; Morbidity - disease rate; Mutation; Organoids; Oxygen; Pathogenesis; Play; Predisposition; Real-Time Systems; Research; Research Personnel; Role; Sampling; System; Testing; Tissue Engineering; Viral; Virulence Factors; Work; drug discovery; drug testing; enteric pathogen; experimental study; flexibility; gastrointestinal; gastrointestinal epithelium; gastrointestinal infection; gut microbiota; human pluripotent stem cell; human stem cells; insight; intestinal epithelium; member; microbiome; microbiota; microorganism interaction; mortality; novel; novel therapeutics; pathogen; public health relevance; response; stem cell biology; terics; uptake

 DESCRIPTION OF THE OVERALL U19 APPLICATION (provided by applicant): Enteric infectious diseases continue to represent a major cause of morbidity and mortality worldwide. In addition to gastrointestinal pathogens that have been known for centuries, there continues to be an emergence of enteric disease agents as a product of manmade and natural changes in the environment. The appearance of antibiotic resistance and the lateral transfer of virulence factors have also impacted our ability to deal with "well known" pathogens. To counter these infectious disease threats, novel methods of studying these pathogens are needed. We have assembled an interdisciplinary team to address the need for novel alternative model systems for enteric diseases research. With expertise in viral and bacterial pathogenesis, immunology, tissue engineering, stem cell biology, infectious diseases and bioengineering, this team will utilize human intestinal or- ganoids (HIOs) generated from human pluripotent stem cells (hPSCs) as a model gut epithelium. Three integrated projects will address the common specific aim of utilizing HIOs as a system to investigate the interaction between the intestinal epithelium, immune cells, microbiota and enteric pathogens. The first project will focus on the interaction of the HIO epithelium with normal members of the gut microbiota and specific enteric pathogens. Changes in the function of both the microbes and the HIO epithelium will be investigated. The second project will focus on interactions between the model epithelium found in the organoids and cellular elements of the immune system. Human immune cells will be allowed to interact with HIOs in both the presence and absence of microbes. The final project will employ a bioengineering approach to create a system that both facilitates the use of HIOs as a platform for scientific discovery and serves as a flexible platform for drug discovery and testing. These three projects will form an integrated cooperative research center that will involve investigators with a wide range of complementary expertise. Successful completion of the three projects will generate a powerful new system to study the biology of enteric disease agents and a platform for the development of novel therapeutics for their control.

 U19 整体应用的描述（由申请人提供）：肠道传染病仍然是全世界发病和死亡的主要原因，除了几个世纪以来已知的胃肠道病原体之外，还不断出现肠道疾病病原体。环境中人为和自然变化的产物和毒力因子的横向转移也影响了我们应对“众所周知”病原体的能力。传染病威胁，我们需要研究这些病原体的新方法，以解决肠道疾病研究对新型替代模型系统的需求，该团队拥有病毒和细菌发病机制、免疫学、组织工程、干细胞生物学、在传染病和生物工程方面，该团队将利用人类多能干细胞 (hPSC) 产生的人类肠道类器官 (HIO) 作为肠道上皮模型，三个综合项目将解决利用 HIO 作为肠道上皮细胞的共同具体目标。研究肠道上皮、免疫细胞、微生物群和肠道病原体之间相互作用的系统第一个项目将重点关注 HIO 上皮与肠道微生物群正常成员和特定肠道病原体功能的变化。第二个项目将研究微生物和 HIO 上皮细胞之间的相互作用，类器官中发现的模型上皮细胞与免疫系统的细胞成分之间的相互作用。最终项目将采用生物工程方法创建一个系统，既促进 HIO 作为科学发现的平台，又作为药物发现和测试的灵活平台。将组建一个综合合作研究中心，由具有广泛互补专业知识的研究人员参与，这三个项目的成功完成将产生一个强大的新系统来研究肠道疾病制剂的生物学，并为开发新疗法提供平台。控制。