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Tytuł pozycji:

Development of a Gut-On-A-Chip Model for High Throughput Disease Modeling and Drug Discovery.

Tytuł:
Development of a Gut-On-A-Chip Model for High Throughput Disease Modeling and Drug Discovery.
Autorzy:
Beaurivage C; Galapagos BV, Zernikedreef 16, 2333 CL Leiden, The Netherlands.; Department of Biomedical Sciences, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
Naumovska E; Department of Biomedical Sciences, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.; Mimetas BV, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands.
Chang YX; Galapagos BV, Zernikedreef 16, 2333 CL Leiden, The Netherlands.
Elstak ED; Galapagos BV, Zernikedreef 16, 2333 CL Leiden, The Netherlands.
Nicolas A; Mimetas BV, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands.
Wouters H; Galapagos BV, Zernikedreef 16, 2333 CL Leiden, The Netherlands.
van Moolenbroek G; Mimetas BV, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands.
Lanz HL; Mimetas BV, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands.
Trietsch SJ; Mimetas BV, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands.
Joore J; Mimetas BV, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands.
Vulto P; Mimetas BV, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands.
Janssen RAJ; Galapagos BV, Zernikedreef 16, 2333 CL Leiden, The Netherlands.
Erdmann KS; Department of Biomedical Sciences, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
Stallen J; Galapagos BV, Zernikedreef 16, 2333 CL Leiden, The Netherlands.
Kurek D; Mimetas BV, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands.
Źródło:
International journal of molecular sciences [Int J Mol Sci] 2019 Nov 12; Vol. 20 (22). Date of Electronic Publication: 2019 Nov 12.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Original Publication: Basel, Switzerland : MDPI, [2000-
MeSH Terms:
Drug Discovery*
Inflammatory Bowel Diseases*/drug therapy
Inflammatory Bowel Diseases*/genetics
Inflammatory Bowel Diseases*/metabolism
Inflammatory Bowel Diseases*/pathology
Microchip Analytical Procedures*
Models, Biological*
Caco-2 Cells ; Drug Evaluation, Preclinical ; Gene Knockout Techniques ; Humans ; Lab-On-A-Chip Devices ; Myeloid Differentiation Factor 88/genetics ; Myeloid Differentiation Factor 88/metabolism ; Transcription Factor RelA/genetics ; Transcription Factor RelA/metabolism
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Grant Information:
674983 Horizon 2020; 641639 Horizon 2020
Contributed Indexing:
Keywords: Organ-on-a-Chip; disease modeling; drug discovery; gut-on-a-chip; inflammation; inflammatory bowel disease; microfluidic
Substance Nomenclature:
0 (MYD88 protein, human)
0 (Myeloid Differentiation Factor 88)
0 (RELA protein, human)
0 (Transcription Factor RelA)
Entry Date(s):
Date Created: 20191116 Date Completed: 20200401 Latest Revision: 20200401
Update Code:
20240105
PubMed Central ID:
PMC6888156
DOI:
10.3390/ijms20225661
PMID:
31726729
Czasopismo naukowe
A common bottleneck in any drug development process is finding sufficiently accurate models that capture key aspects of disease development and progression. Conventional drug screening models often rely on simple 2D culture systems that fail to recapitulate the complexity of the organ situation. In this study, we show the application of a robust high throughput 3D gut-on-a-chip model for investigating hallmarks of inflammatory bowel disease (IBD). Using the OrganoPlate platform, we subjected enterocyte-like cells to an immune-relevant inflammatory trigger in order to recapitulate key events of IBD and to further investigate the suitability of this model for compound discovery and target validation activities. The induction of inflammatory conditions caused a loss of barrier function of the intestinal epithelium and its activation by increased cytokine production, two events observed in IBD physiopathology. More importantly, anti-inflammatory compound exposure prevented the loss of barrier function and the increased cytokine release. Furthermore, knockdown of key inflammatory regulators RELA and MYD88 through on-chip adenoviral shRNA transduction alleviated IBD phenotype by decreasing cytokine production. In summary, we demonstrate the routine use of a gut-on-a-chip platform for disease-specific aspects modeling. The approach can be used for larger scale disease modeling, target validation and drug discovery purposes.
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