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Appropriately simulating the 3-D environment in which organs and tissues normally function is necessary for development of cultures that realistically resemble in vivo tissues and organs. At the same time, it is essential to accommodate experimental flexibility and high throughput analysis. For these reasons, the availability of reliable, reproducible 3-D tissue assemblies that effectively model the structure and function of human tissues holds tremendous promise for infectious disease research. Our lab has used innovative bioengineering technology developed by NASA to establish biologically meaningful 3-D models of human tissues that recapitulate many aspects of the differentiated structure and function of the parental tissue in vivo. We have applied these models to study infectious disease caused by a variety of microbial pathogens (bacterial and viral). A variety of different 3-D models have been established by our lab that have been/are being used in infection studies - including small intestine, colon, lung, placenta, bladder, periodontal ligament, vaginal and neuronal models. Published work from our lab has shown that our 3-D models respond to infection with bacterial and viral pathogens in ways that reflect the infection process in vivo.
Our establishment and characterization of biologically meaningful 3-D cultures of human cells and tissues and their practical application in modeling infectious disease provide specific examples of how the study of bacterial and viral pathogenesis can benefit from an appropriate, biologically meaningful 3-D tissue model. In addition, we continue to enhance the physiological relevance of our 3-D cell culture models by developing multicellular 3-D co-culture models. Thus, in our hierarchical tissue modeling approaches, we strive to recapitulate both the 3-D architecture and multicellular complexity that is inherent in functional tissues in vivo. These physiologically relevant model systems are reproducible, experimentally flexible, cost effective, and offer high throughput platforms that hold promise for the translational advancement of human health.
Our work with the 3-D model systems established and funded by this grant and their subsequent application to infectious disease studies has: 1) Facilitated meaningful dissection of molecular mechanisms of infectious disease caused by bacterial and viral pathogens, including the identity of novel host biosignatures in response to infection (including Salmonella sp, Norwalk virus, and Pseudomonas aeruginosa). 2) Allowed the study of infectious disease agents that lack suitable cell culture and animal models - Norwalk virus 3) Shown exciting potential for the development of novel diagnostics, vaccines, and therapeutic strategies for prevention & treatment
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Articles in Peer-reviewed Journals
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Höner zu Bentrup K, Ramamurthy R, Ott CM, Emami K, Nelman-Gonzalez M, Wilson JW, Richter EG, Goodwin TJ, Alexander JS, Pierson DL, Pellis N, Buchanan KL, Nickerson CA. "Three-dimensional organotypic models of human colonic epithelium to study the early stages of enteric salmonellosis." Microbes Infect. 2006 Jun;8(7):1813-25. PMID: 16730210 , Jun-2006
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Articles in Peer-reviewed Journals
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Straub TM, Höner zu Bentrup K, Orosz-Coghlan P, Dohnalkova A, Mayer BK, Bartholomew RA, Valdez CO, Bruckner-Lea CJ, Gerba CP, Abbaszadegan M, Nickerson CA. "In vitro cell culture infectivity assay for human noroviruses." Emerg Infect Dis. 2007 Mar;13(3):396-403. PMID: 17552092 , Mar-2007
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Articles in Peer-reviewed Journals
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Myers TA, Nickerson CA, Kaushal D, Ott CM, Höner zu Bentrup K, Ramamurthy R, Nelman-Gonzalez M, Pierson DL, Philipp MT. "Closing the phenotypic gap between transformed neuronal cell lines in culture and untransformed neurons." J Neurosci Methods. 2008 Sep 15;174(1):31-41. PMID: 18672002 , Sep-2008
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Articles in Peer-reviewed Journals
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Carterson AJ, Höner zu Bentrup K, Ott CM, Clarke MS, Pierson DL, Vanderburg CR, Buchanan KL, Nickerson CA, Schurr MJ. "A549 lung epithelial cells grown as three-dimensional aggregates: alternative tissue culture model for Pseudomonas aeruginosa pathogenesis." Infect Immun. 2005 Feb;73(2):1129-40. PMID: 15664956 , Feb-2005
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Articles in Peer-reviewed Journals
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LaMarca HL, Ott CM, Höner Zu Bentrup K, Leblanc CL, Pierson DL, Nelson AB, Scandurro AB, Whitley GS, Nickerson CA, Morris CA. "Three-dimensional growth of extravillous cytotrophoblasts promotes differentiation and invasion." Placenta. 2005 Nov;26(10):709-20. PMID: 16226120 , Nov-2005
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Articles in Peer-reviewed Journals
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Nickerson CA, Honer zu Bentrup K, Ott CM. "Three-dimensional cell culture models for drug discovery and infectious disease." Bioforum Europe 2005 Nov;6:34-6. , Nov-2005
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Articles in Peer-reviewed Journals
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Nickerson CA, Richter EG, Ott CM. "Studying host-pathogen interactions in 3-D: organotypic models for infectious disease and drug development." J Neuroimmune Pharmacol. 2007 Mar;2(1):26-31. Review. PMID: 18040823 , Mar-2007
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Articles in Peer-reviewed Journals
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Crabbé A, Sarker SF, Van Houdt R, Ott CM, Leys N, Cornelis P, Nickerson CA. "Alveolar epithelium protects macrophages from quorum sensing-induced cytotoxicity in a three-dimensional co-culture model." Cell Microbiol. 2011 Mar;13(3):469-81. http://dx.doi.org/10.1111/j.1462-5822.2010.01548.x Epub 2010 Nov 25. PMID: 21054742 , Mar-2011
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Articles in Peer-reviewed Journals
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Barrila J, Radtke AL, Crabbé A, Sarker SF, Herbst-Kralovetz MM, Ott CM, Nickerson CA. "Organotypic 3D cell culture models: using the rotating wall vessel to study host-pathogen interactions." Nat Rev Microbiol. 2010 Nov;8(11):791-801. PMID: 20948552 , Nov-2010
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Articles in Peer-reviewed Journals
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Radtke AL, Wilson JW, Sarker S, Nickerson CA. "Analysis of interactions of Salmonella type three secretion mutants with 3-D intestinal epithelial cells." PLoS One. 2010 Dec 29;5(12):e15750. PMID: 21206750
, Dec-2010
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Articles in Peer-reviewed Journals
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Skardal A, Sarker SF, Crabbé A, Nickerson CA, Prestwich GD. "The generation of 3-D tissue models based on hyaluronan hydrogel-coated microcarriers within a rotating wall vessel bioreactor." Biomaterials. 2010 Nov;31(32):8426-35. Epub 2010 Aug 7. PMID: 20692703
, Nov-2010
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Articles in Peer-reviewed Journals
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Crabbé A, Pycke B, Van Houdt R, Monsieurs P, Nickerson C, Leys N, Cornelis P. "Response of Pseudomonas aeruginosa PAO1 to low shear modelled microgravity involves AlgU regulation." Environ Microbiol. 2010 Jun;12(6):1545-64. Epub 2010 Mar 5. PMID: 20236169
, Jun-2010
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