Regulatory mechanisms of innate immune signaling in zebrafish embryos

Leiden Repository

Regulatory mechanisms of innate immune signaling in zebrafish embryos

Title: Regulatory mechanisms of innate immune signaling in zebrafish embryos
Author: Kanwal, Zakia
Publisher: Molecular Cell Biology of the Institute of Biology (IBL), Faculty of Science, Leiden University
Issue Date: 2012-12-12
Keywords: Deep sequencing
Infection
Inflammation
Innate immunity
MicroRNA
Mycobacterium marinum
Negative regulators
Ptpn6 knockdown
Salmonella typhimurium
Transcriptomics
Abstract: The work presented in this thesis has provided new insights into the mechanisms involved in the regulation of innate immune responses in zebrafish embryos. Furthermore, cell-specific transcriptome profiling studies identified novel marker genes for distinguishing immune cell types, which is highly useful information to fulfill the demand for new fluorescent reporter lines and lineage-specific antibodies in the zebrafish model. We have shown that Ptpn6, a protein tyrosine phosphatase homolog of human SHP1, functions as a critical negative regulator, required for a properly balanced innate immune response and for controlling infections with bacterial pathogens. In Salmonella typhimurium infection, ptpn6 deficiency caused a general hyperinduction of pro-inflammatory genes, which was contraproductive as it impaired the infection control. In Mycobacterium marinum infection, a more specific effect of ptpn6 deficiency on matrix metalloproteinase gene expression was found as a major underlying cause of increased bacterial burden. We further concluded that Ptpn6 functions as a much stronger negative regulator than infection-inducible miRNAs of the miR-146 family, which may be involved in more subtle fine-tuning of the innate immune response. Knowledge about the distinct roles of Ptpn6 and miR-146 miRNAs has practical applicability in regard to their potential as therapeutic targets for inflammatory diseases and cancer.
Description: Promotor: H.P. Spaink, Co-promotor: A.H. Meijer
With summary in Dutch
Faculty: Faculteit der Wiskunde en Natuurwetenschappen
Citation: Kanwal, Z., 2012, Doctoral thesis, Leiden University
ISBN: 9789462032064
Sponsor: Smart Mix Program of The Netherlands Ministry of Economic Affairs and the Ministry of Education, Culture and Science; European Commission 7th framework programme, project ZF-HEALTH (HEALTH-F4-2010-242048); European Marie-Curie Initial Training Network FishForPharma (PITN-GA-2011-289209); European Commission 6th Framework Project ZF-TOOLS (LSHG-CT-2006-037220); Higher Education Commission of the Pakistan Government.
Handle: http://hdl.handle.net/1887/20272
 

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