Epithelial interactions with indigenous and pathogenic microbes

上皮与本土微生物和病原微生物的相互作用

• 批准号: 8855061
• 负责人: VINCENT B YOUNG
• 金额: $ 39.03万
• 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/8855061
• 关键词: 3-Dimensional; Adherens Junction; Affect; Animal Model; Architecture; Bacteria; Bacterial Antigens; Biological Models; Cell Culture System; Cell Culture Techniques; Cell physiology; Cells; Clinical Trials; Clostridium difficile; Communicable Diseases; Communities; Complex; Data; Development; Disease; Ecosystem; Enteral; Enterocytes; Environment; Epithelial; Epithelium; Equilibrium; Escherichia coli; Food; Gene Expression; Germ-Free; Gnotobiotic; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Homeostasis; Human; Human Engineering; Immune system; In Vitro; Indigenous; Individual; Infection; Intestines; Knowledge; Lead; Mesenchyme; Microbe; Modeling; Molecular; Mus; Norovirus; Nutrient; Organism; Organoids; Physiological; Physiology; Pluripotent Stem Cells; Probiotics; Proteins; Salmonella enterica; Signal Transduction; Small Intestines; Stem cells; Structure; Symbiosis; System; Testing; Therapeutic; Tight Junctions; Tissues; Toxin; Viral; Virus; Water; Work; base; cell transformation; cell type; commensal microbes; enteric pathogen; exposed human population; food antigen; foodborne pathogen; gastrointestinal system; human disease; immune function; intestinal epithelium; intestinal homeostasis; microorganism interaction; multidisciplinary; novel; nutrient absorption; pathogen; response

PROJECT SUMMARY/ABSTRACT The intestinal epithelium is comprised of a single epithelial layer with both absorptive and secretory functions and is responsible for nutrient absorption. Additionally it is in constant contact with the abundant and diverse indigenous microbiota that inhabits the intestinal lumen. The epithelium and the microbiota exists in a remarkably stable, bal- anced symbiosis. This symbiosis is responsible for homeostasis of the intestinal ecosystem, and disturbances in this relationship has been associated with a wide variety of disease states. While animal models and the use of germ-free and gnotobiotic mice have led to remarkable advances in our understanding of host-microbial interac- tions, species-specific differences have made it difficult to study many human enteric pathogens, and suitable in vitro cell culture models that accurately represent human physiology are severely lacking. We have recently de- scribed an in vitro system that accurately reflects both the complex cellular makeup and the topological organization of the human intestine. Using human pluripotent stem cells (hPSCs), we have generated 3-dimensional (3D) intes- tinal units called Human Intestinal Organoids (HIOs). HIOs contain both intestinal epithelium and mesenchyme and are comprised of all of the different cell types found in the small intestine. HIOs have already proven to be a powerful system to study human intestinal development. Our preliminary results demonstrate that HIOs are also an excellent system to study how enteric pathogens affect the host epithelium. Therefore, the overarching goal of this project is to determine how specific enteric pathogens and normal microbiota affect the host HIO epithelium at the cellular and molecular level, and to determine how complex host-microbiota-pathogen relationships are estab- lished and maintained within the HIO. We propose to 1) investigate how interaction between commensal microbes and the HIO epithelium affects each partner in this symbiosis, 2) determine how contact pathogens affects the physiology of the HIO epithelium and 3) determine if contact with commensal microbes will alter the patho- gen/epithelium interaction. To accomplish these specific aims, we have established a multidisciplinary team that will examine the complex relationship between the HIO epithelium, the indigenous microbiota and viral and bacterial enteric pathogens.

项目总结/摘要 肠上皮由具有吸收和分泌功能的单一上皮层组成， 负责营养吸收。此外，它还与丰富多样的土著人民保持着不断的联系。 微生物群，栖息在肠腔。上皮细胞和微生物群存在于一个非常稳定的，平衡的， 先进的共生这种共生关系负责肠道生态系统的内稳态，以及肠道内的干扰。 这种关系与多种疾病状态有关。虽然动物模型和使用 无菌和无菌小鼠的出现，使我们对宿主-微生物相互作用的理解取得了显著进展， 此外，物种特异性差异使得研究许多人类肠道病原体变得困难，并且适合于 严重缺乏准确代表人类生理学的体外细胞培养模型。我们最近- 描述了一个体外系统，准确地反映了复杂的细胞组成和拓扑组织 人体肠道使用人类多能干细胞（hPSC），我们已经产生了三维（3D）intes- 人类肠道类器官（Human Intestinal Organoids，HIOs）HIOs包含肠上皮和间充质 并且由小肠中发现的所有不同类型的细胞组成。HIO已经被证明是一个 研究人类肠道发育的强大系统。我们的初步结果表明，HIO也是一个 这是研究肠道病原体如何影响宿主上皮的绝佳系统。因此， 该项目旨在确定特定肠道病原体和正常微生物群如何影响宿主HIO上皮细胞， 细胞和分子水平，并确定复杂的宿主-微生物群-病原体关系是如何建立的， 在HIO中创建和维护。我们建议1）研究浮游微生物之间的相互作用 和HIO上皮细胞影响这种共生关系中的每一个伙伴，2）确定接触病原体如何影响 HIO上皮的生理学和3）确定与肠道微生物的接触是否会改变病理学， 生殖/上皮相互作用。为了实现这些具体目标，我们成立了一个多学科团队， 研究HIO上皮细胞、本土微生物群和病毒和细菌之间的复杂关系 肠道病原体