This application requests funding of a NAMSED Cooperative Research Center (called CRC for simplicity) in the Texas Medical Center. This CRC's primary objective will be achieved through the collaborative efforts of a multidisciplinary, integrated team of basic scientists, biomedical engineers and a physician scientist who are at three institutions (Baylor College of Medicine (BCM), Rice University, the MD Anderson Cancer Center). The overall goal of this CRC is to create the first ex-vivo mini-gut model systems that are physiologically active and mimic many aspects of human intestine. We will use human intestinal enteroids (HIEs) derived from human intestinal biopsies to address key questions about human enteric disease caused by microorganisms that produce human diarrheal disease and lead to ~4% of all deaths worldwide. New models that adequately reflect relevant human physiology, pathophysiology and natural host-pathogen interactions are critically needed because most human pathogens that cause diarrheal disease lack animal models that accurately mimic the human disease. This CRC application integrates a team with multidisciplinary expertise including basic and translational research and innovation in virology, bacteriology including the microbiome, genomics, developmental biology and physiology, biomedical engineering and biomaterial development of engineered tissues including in vitro vascularization and 3D printing, infectious disease epidemiology and clinical microbiology. This CBC will consist of 3 Projects and 3 Core facilities. Project 1 will use HIEs to analyze genetically-regulated host restriction to human rotavirus and vaccine replication and to define epithelial cell responses that lead to pathophysiology. Project 2 will use HIEs to understand the pathogenesis of infections with diarrheagenic E. coli including factors that characterize differences between acute and chronic infections, tissue tropism and mechanisms of pathology. Project 3 will combine tissue engineering, biomaterial design, and mechanobiology to develop tailored, biofunctional platforms for HIEs that can be mechanically stimulated and that will promote cell and tissue polarity as well as the full crypt-villus differentiation to facilitate infection with commensals and enteropathogens. These 3 interrelated and synergistic projects will be supported by the specialized and intellectual contributions of 3 Core Facilities: the Administrative Core, Human Enteroid Core, and Genomics and Microbiome Core. Two Pilot Developmental Research Projects will be supported with one being funded by BCM. The success of this CRC depends on the complementary expertise of the individual investigators and center leaders who are senior scientists-administrators experienced in directing interactive, multidisciplinary programs. Collaboration and iterative feedback between biomedical engineers, local biologists and other NAMSED investigators will facilitate progress towards developing an ideal system that will be state of the art yet sufficiently simple for routin use in infectious disease laboratories and adequately robust for use in pre-clinical studies.
The ingestion of contaminated food or water can lead to severe infection of the intestine with pathogenic bacteria and viruses. These microorganisms can cause life-threatening diarrhea, kidney damage, and dehydration. In this work, we study new model systems, grown in specialized culture dishes in the lab, which can help researchers understand how these viruses and bacteria cause disease. These new models will be developed for routine use in infectious disease labs.
|Saxena, Kapil; Simon, Lukas M; Zeng, Xi-Lei et al. (2017) A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection. Proc Natl Acad Sci U S A 114:E570-E579|
|Crawford, Sue E; Ramani, Sasirekha; Tate, Jacqueline E et al. (2017) Rotavirus infection. Nat Rev Dis Primers 3:17083|
|Vernetti, Lawrence; Gough, Albert; Baetz, Nicholas et al. (2017) Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle. Sci Rep 7:42296|
|Zou, Winnie Y; Blutt, Sarah E; Crawford, Sue E et al. (2017) Human Intestinal Enteroids: New Models to Study Gastrointestinal Virus Infections. Methods Mol Biol :|
|Blutt, Sarah E; Broughman, James R; Zou, Winnie et al. (2017) Gastrointestinal microphysiological systems. Exp Biol Med (Maywood) 242:1633-1642|
|Poole, Nina M; Green, Sabrina I; Rajan, Anubama et al. (2017) Role for FimH in Extraintestinal Pathogenic Escherichia coli Invasion and Translocation through the Intestinal Epithelium. Infect Immun 85:|
|Chen, Ying; Zhou, Wenda; Roh, Terrence et al. (2017) In vitro enteroid-derived three-dimensional tissue model of human small intestinal epithelium with innate immune responses. PLoS One 12:e0187880|
|Laucirica, Daniel R; Triantis, Vassilis; Schoemaker, Ruud et al. (2017) Milk Oligosaccharides Inhibit Human Rotavirus Infectivity in MA104 Cells. J Nutr 147:1709-1714|
|Green, Sabrina I; Kaelber, Jason T; Ma, Li et al. (2017) Bacteriophages from ExPEC Reservoirs Kill Pandemic Multidrug-Resistant Strains of Clonal Group ST131 in Animal Models of Bacteremia. Sci Rep 7:46151|
|In, Julie G; Foulke-Abel, Jennifer; Estes, Mary K et al. (2016) Human mini-guts: new insights into intestinal physiology and host-pathogen interactions. Nat Rev Gastroenterol Hepatol 13:633-642|
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