| 1. |
- Hede, Sanna-Maria, et al.
(author)
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GFAP promoter driven transgenic expression of PDGFB in the mouse brain leads to glioblastoma in a Trp53 null background
- 2009
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In: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 57:11, s. 1143-1153
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Journal article (peer-reviewed)abstract
- Glioblastomas are the most common and malignant astrocytic brain tumors in human adults. The tumor suppressor gene TP53 is commonly mutated and/or lost in astrocytic brain tumors and the TP53 alterations are often found in combination with excessive growth factor signaling via PDGF/PDGFRalpha. Here, we have generated transgenic mice over-expressing human PDGFB in brain, under control of the human GFAP promoter. These mice showed no phenotype, but on a Trp53 null background a majority of them developed brain tumors. This occurred at 2-6 months of age and tumors displayed human glioblastoma-like features with integrated development of Pdgfralpha+ tumor cells and Pdgfrbeta+/Nestin+ vasculature. The transgene was expressed in subependymal astrocytic cells, in glia limitans, and in astrocytes throughout the brain substance, and subsequently, microscopic tumor lesions were initiated equally in all these areas. With tumor size, there was an increase in Nestin positivity and variability in lineage markers. These results indicate an unexpected plasticity of all astrocytic cells in the adult brain, not only of SVZ cells. The results also indicate a contribution of widely distributed Pdgfralpha+ precursor cells in the tumorigenic process.
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| 2. |
- Larsson, Erik, 1975, et al.
(author)
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Discovery of microvascular miRNAs using public gene expression data : miR-145 is expressed in pericytes and is a regulator of Fli1
- 2009
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In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 1:11, s. 108-
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Journal article (peer-reviewed)abstract
- BACKGROUNDA function for the microRNA (miRNA) pathway in vascular development and angiogenesis has been firmly established. miRNAs with selective expression in the vasculature are attractive as possible targets in miRNA-based therapies. However, little is known about the expression of miRNAs in microvessels in vivo. Here, we identified candidate microvascular-selective miRNAs by screening public miRNA expression datasets.METHODSBioinformatics predictions of microvascular-selective expression were validated with real-time quantitative reverse transcription PCR on purified microvascular fragments from mouse. Pericyte expression was shown with in situ hybridization on tissue sections. Target sites were identified with 3' UTR luciferase assays, and migration was tested in a microfluid chemotaxis chamber.RESULTSmiR-145, miR-126, miR-24, and miR-23a were selectively expressed in microvascular fragments isolated from a range of tissues. In situ hybridization and analysis of Pdgfb retention motif mutant mice demonstrated predominant expression of miR-145 in pericytes. We identified the Ets transcription factor Friend leukemia virus integration 1 (Fli1) as a miR-145 target, and showed that elevated levels of miR-145 reduced migration of microvascular cells in response to growth factor gradients in vitro.CONCLUSIONSmiR-126, miR-24 and miR-23a are selectively expressed in microvascular endothelial cells in vivo, whereas miR-145 is expressed in pericytes. miR-145 targets the hematopoietic transcription factor Fli1 and blocks migration in response to growth factor gradients. Our findings have implications for vascular disease and provide necessary information for future drug design against miRNAs with selective expression in the microvasculature.
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| 3. |
- Sun, Ying, et al.
(author)
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Glomerular Transcriptome Changes Associated with Lipopolysaccharide-Induced Proteinuria
- 2009
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In: American Journal of Nephrology. - : S. Karger AG. - 0250-8095 .- 1421-9670. ; 29:6, s. 558-570
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Journal article (peer-reviewed)abstract
- Background: Global gene expression patterns have recently been characterized in normal glomeruli, but gene expression changes that accompany glomerular disease remain poorly characterized. Method: Here, we mapped global glomerular gene expression profile changes occurring in conjunction with lipopolysaccharide (LPS)-induced proteinuria in mice. Results: We observed dramatic transcriptional reprogramming in glomeruli in response to LPS, representing some 20% of all genes and about 45% of the genes that are normally highly expressed in glomeruli. Bioinformatic analysis revealed significant changes in transcripts encoding proteins involved in the regulation of adherence junctions, actin cytoskeleton and survival in podocytes. In the LPS-treated mice, we observed dysregulation of genes expressed in glomerular endothelial and mesangial cells and in podocytes, there was also a significant decrease in podocyte number. Moreover, collagen alpha 1, alpha 2 (IV) and laminin 10 (laminin alpha 5 beta 1 gamma 1), which are expressed in immature glomeruli, were upregulated in the glomeruli of LPS-treated mice, suggesting remodeling of the glomerular basement membrane and activation of mesangial cells. By superimposing the LPS-induced changes onto GlomNet, a protein-protein interaction network was predicted for podocyte proteins affected by LPS. Conclusions: The detected changes in glomerular gene expression and their involvement in protein interaction networks provide putative markers for early and transient glomerular injury and proteinuria. Copyright (c) 2009 S. Karger AG, Basel
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| 4. |
- Wallgard, Elisabet, et al.
(author)
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Identification of a core set of 58 gene transcripts with broad and specific expression in the microvasculature.
- 2008
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In: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636 .- 1079-5642. ; 28:8, s. 1469-76
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Pathological angiogenesis is an integral component of many diseases. Antiangiogenesis and vascular targeting are therefore promising new therapeutic principles. However, few endothelial-specific putative drug targets have been identified, and information is still limited about endothelial-specific molecular processes. Here we aimed at determining the endothelial cell-specific core transcriptome in vivo. METHODS AND RESULTS: Analysis of publicly available microarray data identified a mixed vascular/lung cluster of 132 genes that correlated with known endothelial markers. Filtering against kidney glomerular/nonglomerular and brain vascular/nonvascular microarray profiles separated contaminating lung markers, leaving 58 genes with broad and specific microvascular expression. More than half of these have not previously been linked to endothelial functions or studied in detail before. The endothelial cell-specific expression of a selected subset of these, Eltd1, Gpr116, Ramp2, Slc9a3r2, Slc43a3, Rasip1, and NM_023516, was confirmed by real-time quantitative polymerase chain reaction and/or immunohistochemistry. CONCLUSIONS: We have used a combination of publicly available and own microarray data to identify 58 gene transcripts with broad yet specific expression in microvascular endothelium. Most of these have unknown functions, but many of them are predicted to be cell surface expressed or implicated in cell signaling processes and should therefore be explored as putative microvascular drug targets.
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