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.

Public Health Relevance

Infections of the gastrointestinal tract with microbes remains a significant health problem. To develop a new method to study these important infections, we will use a recently developed method that involves the creation of organoids from human stem cells. Organoids are hollow balls of cells that resemble the lining of the intestines. We have shown that we can infect organoids with microbes. We will study how microbes affect the human intestinal organoid epithelium and how the microbes themselves change after contact with the human epithelium. We will also look at how the cells of the immune system interact with the organoid, with and without the presence of microbes. Finally, we will use bioengineering to develop microfluidic systems that will allow us to create a scalable model that can be used to study enteric pathogenesis, or that can be used in the development and testing of new treatments for enteric infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI116482-04
Application #
9450368
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Alexander, William A
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Chin, Alana M; Hill, David R; Aurora, Megan et al. (2017) Morphogenesis and maturation of the embryonic and postnatal intestine. Semin Cell Dev Biol 66:81-93
Young, Vincent B (2017) Treatment With Fecal Microbiota Transplantation: The Need for Complete Methodological Reporting for Clinical Trials. Ann Intern Med 167:61-62
Lesher-Pérez, Sasha Cai; Kim, Ge-Ah; Kuo, Chuan-Hsien et al. (2017) Dispersible oxygen microsensors map oxygen gradients in three-dimensional cell cultures. Biomater Sci 5:2106-2113
Hill, David R; Huang, Sha; Nagy, Melinda S et al. (2017) Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium. Elife 6:
Cruz-Acuña, Ricardo; Quirós, Miguel; Farkas, Attila E et al. (2017) Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. Nat Cell Biol 19:1326-1335
Tsai, Yu-Hwai; Nattiv, Roy; Dedhia, Priya H et al. (2017) In vitro patterning of pluripotent stem cell-derived intestine recapitulates in vivo human development. Development 144:1045-1055
Kim, Ge-Ah; Spence, Jason R; Takayama, Shuichi (2017) Bioengineering for intestinal organoid cultures. Curr Opin Biotechnol 47:51-58
Dedhia, Priya H; Bertaux-Skeirik, Nina; Zavros, Yana et al. (2016) Organoid Models of Human Gastrointestinal Development and Disease. Gastroenterology 150:1098-1112
Leslie, Jhansi L; Young, Vincent B (2016) A whole new ball game: Stem cell-derived epithelia in the study of host-microbe interactions. Anaerobe 37:25-8
Aurora, Megan; Spence, Jason R (2016) hPSC-derived lung and intestinal organoids as models of human fetal tissue. Dev Biol 420:230-238

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