Global gene expression profile progression in Gaucher disease mouse models

Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure. To elucidate this pathogenic pathway, de...

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Bibliographic Details
Published in:	BMC genomics Vol. 12; no. 1; p. 20
Main Authors:	Xu, You-Hai, Jia, Li, Quinn, Brian, Zamzow, Matthew, Stringer, Keith, Aronow, Bruce, Sun, Ying, Zhang, Wujuan, Setchell, Kenneth D R, Grabowski, Gregory A
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 11-01-2011 BioMed Central BMC
Subjects:	Animals Children & youth Development and progression Disease Models, Animal Gaucher Disease - genetics Gaucher Disease - metabolism Gaucher's disease Gene expression Gene Expression Profiling Genetic aspects Genomics Glycosphingolipids - metabolism Histology Lungs Macrophages Mice Mice, Knockout Oligonucleotide Array Sequence Analysis Pathogenesis Physiological aspects Reverse Transcriptase Polymerase Chain Reaction Studies United States
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Summary:	Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure. To elucidate this pathogenic pathway, developmental global gene expression analyses were conducted in distinct Gba1 point-mutated mice (V394L/V394L and D409 V/null). About 0.9 to 3% of genes had altered expression patterns (≥ ± 1.8 fold change), representing several categories, but particularly macrophage activation and immune response genes. Time course analyses (12 to 28 wk) of INFγ-regulated pro-inflammatory (13) and IL-4-regulated anti-inflammatory (11) cytokine/mediator networks showed tissue differential profiles in the lung and liver of the Gba1 mutant mice, implying that the lipid-storage macrophages were not functionally inert. The time course alterations of the INFγ and IL-4 pathways were similar, but varied in degree in these tissues and with the Gba1 mutation. Biochemical and pathological analyses demonstrated direct relationships between the degree of tissue glucosylceramides and the gene expression profile alterations. These analyses implicate IFNγ-regulated pro-inflammatory and IL-4-regulated anti-inflammatory networks in differential disease progression with implications for understanding the Gaucher disease course and pathophysiology.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1471-2164 1471-2164
DOI:	10.1186/1471-2164-12-20