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

 U19申请的总体描述(由申请人提供)：肠道传染病仍然是全球发病率和死亡率的主要原因。除了几个世纪以来已知的胃肠道病原体外，作为环境人为和自然变化的产物，肠道疾病病原体继续出现。抗生素抗药性的出现和毒力因子的横向转移也影响了我们应对众所周知的病原体的能力。为了应对这些传染病威胁，需要研究这些病原体的新方法。我们已经组建了一个跨学科的团队，以满足肠道疾病研究对新的替代模型系统的需求。凭借在病毒和细菌发病机制、免疫学、组织工程学、干细胞生物学、传染病和生物工程方面的专业知识，该团队将利用由人类多能干细胞(HPSCs)生成的人肠道或类固醇(HIO)作为肠道上皮细胞的模型。三个综合项目将解决共同的具体目标，即利用HIOS作为一个系统来研究肠道上皮、免疫细胞、微生物区系和肠道病原体之间的相互作用。第一个项目将侧重于HIO上皮与肠道微生物区系的正常成员和特定肠道病原体的相互作用。将研究微生物和HIO上皮功能的变化。第二个项目将专注于在有机体中发现的模型上皮与免疫系统的细胞元素之间的相互作用。人类免疫细胞将被允许在存在和不存在微生物的情况下与HIO相互作用。最后一个项目将采用生物工程方法来创建一个系统，该系统既可促进使用高密度有机化合物作为科学发现的平台，又可作为药物发现和测试的灵活平台。这三个项目将组成一个综合合作研究中心，该中心将涉及具有广泛互补专业知识的研究人员。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病原体的生物学，并为开发用于控制它们的新疗法提供一个平台。

 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.