Knockout mice with pituitary malformations help identify human cases of hypopituitarism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1032055 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26515800.fastq.gz | Fastqsanger.gz | |||
| SRR26515801.fastq.gz | Fastqsanger.gz | |||
| SRR26515802.fastq.gz | Fastqsanger.gz | |||
| SRR26515803.fastq.gz | Fastqsanger.gz | |||
| SRR26515799_1.fastq.gz | Fastqsanger.gz |
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Project description:Gonadotroph adenomas comprise 15M-bM-^@M-^S40 % of all pituitary tumors, are usually non-functioning and are often large and invasive at presentation. Surgery is the first-choice treatment, but complete resection is not always achieved, leading to high recurrence rates. As gonadotroph adenomas poorly respond to conventional pharmacological therapies, novel treatment strategies are needed. Their identification has been hampered by our incomplete understanding of the molecular pathogenesis of these tumors. Recently, we demM-BM-,onstrated that MENX-affected rats develop gonadotroph adenomas closely resembling their human counterparts. To discover new genes/pathways involved in gonadotroph cells tumorigenesis, we performed transcriptome profiling of rat tumors versus normal pituitary. Adenomas showed overrepM-BM-,resentation of genes involved in cell cycle, development, cell differentiation/proliferation, and lipid metabolism. BioinforM-BM-,matic analysis identified downstream targets of the transcripM-BM-,tion factor SF-1 as being up-regulated in rat (and human) adenomas. Meta-analyses demonstrated remarkable similariM-BM-,ties between gonadotroph adenomas in rats and humans, and highlighted common dysregulated genes, several of which were not previously implicated in pituitary tumorigenesis. Two such genes, CYP11A1 and NUSAP1, were analyzed in 39 human gonadotroph adenomas by qRT-PCR and found to be up-regulated in 77 and 95 % of cases, respectively. Immunohistochemistry detected high P450scc (encoded by CYP11A1) and NuSAP expression in 18 human gonadoM-BM-,troph tumors. In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma priM-BM-,mary cells and cell lines. Our studies reveal clues about the molecular mechanisms driving rat and human gonadotroph adenomas development, and may help identify previously unexplored biomarkers for clinical use. We compared five control animals and 16 homozygous mutants (p27Kip1/Cdknb1)
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Project description:Gonadotroph adenomas comprise 15–40 % of all pituitary tumors, are usually non-functioning and are often large and invasive at presentation. Surgery is the first-choice treatment, but complete resection is not always achieved, leading to high recurrence rates. As gonadotroph adenomas poorly respond to conventional pharmacological therapies, novel treatment strategies are needed. Their identification has been hampered by our incomplete understanding of the molecular pathogenesis of these tumors. Recently, we dem¬onstrated that MENX-affected rats develop gonadotroph adenomas closely resembling their human counterparts. To discover new genes/pathways involved in gonadotroph cells tumorigenesis, we performed transcriptome profiling of rat tumors versus normal pituitary. Adenomas showed overrep¬resentation of genes involved in cell cycle, development, cell differentiation/proliferation, and lipid metabolism. Bioinfor¬matic analysis identified downstream targets of the transcrip¬tion factor SF-1 as being up-regulated in rat (and human) adenomas. Meta-analyses demonstrated remarkable similari¬ties between gonadotroph adenomas in rats and humans, and highlighted common dysregulated genes, several of which were not previously implicated in pituitary tumorigenesis. Two such genes, CYP11A1 and NUSAP1, were analyzed in 39 human gonadotroph adenomas by qRT-PCR and found to be up-regulated in 77 and 95 % of cases, respectively. Immunohistochemistry detected high P450scc (encoded by CYP11A1) and NuSAP expression in 18 human gonado¬troph tumors. In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma pri¬mary cells and cell lines. Our studies reveal clues about the molecular mechanisms driving rat and human gonadotroph adenomas development, and may help identify previously unexplored biomarkers for clinical use.
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2008-06-15 | E-GEOD-7190 | biostudies-arrayexpress
Project description:Objective: Vascular malformations affect 3% of neonates. Venous malformations (VMs) are the largest group representing more than 50 % of cases. In hereditary forms of VMs gene mutations have been identified, but for the large group of spontaneous forms the primary cause and downstream dysregulated genes are unknown. Methods and Results: We have performed a global comparison of gene expression in slow-flow VMs and normal saphenous veins using human whole genome micro-arrays. Genes of interest were validated with qRT-PCR. Gene expression in the tunica media was studied after laser micro-dissection of small pieces of tissue. Protein expression in endothelial cells (ECs) was studied with antibodies. We detected 511 genes more than 4-fold down- and 112 genes more than 4-fold up-regulated. Notably, chemokines, growth factors, transcription factors and regulators of extra-cellular matrix (ECM) turnover were regulated. We observed activation and arterialization of ECs of the VM proper, whereas ECs of vasa vasorum exhibited up-regulation of inflammation markers. In the tunica media, an altered ECM turnover and composition was found. Conclusions: Our studies demonstrate dysregulated gene expression in tunica interna, media and externa of VMs, and show that each of the three layers represents a reactive compartment. The dysregulated genes may serve as therapeutic targets. Keywords: disease analysis
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