Gene expression profiles in solid and cystic central nervous system hemangioblastomas
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE148216 | GEO | 2020/04/15
REPOSITORIES: GEO
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Project description:Initial cysts that are formed upon Pkd1 loss in mice impose persistent stress on surrounding tissue and trigger a cystic snowball effect, in which local aberrant PKD-related signaling increases the likelihood of new cyst formation, ultimately leading to accelerated disease progression. Although many pathways have been associated with PKD progression, the knowledge of early changes near initial cysts is limited. To perform an unbiased analysis of transcriptomic alterations in the cyst microenvironment, microdomains were collected from kidney sections of iKsp-Pkd1del mice with scattered Pkd1-deletion using Laser Capture Microdissection. These microdomains were defined as F4/80-low cystic, representing early alterations in the cyst microenvironment, F4/80-high cystic, with more advanced alterations, or non-cystic. RNA sequencing and differential gene expression analysis revealed 953 and 8088 dysregulated genes in the F4/80-low and F4/80-high cyst microenvironment, respectively, when compared to non-cystic microdomains. In the early cyst microenvironment, several injury-repair, growth, and tissue remodeling-related pathways were activated, accompanied by mild metabolic changes. In the more advanced F4/80-high microdomains, these pathways were potentiated and the metabolism was highly dysregulated. Upstream regulator analysis revealed a series of paracrine factors with increased activity in the early cyst microenvironment, including TNFSF12 and OSM. In line with the upstream regulator analysis, TWEAK and Oncostatin-M promoted cell proliferation and inflammatory gene expression in renal epithelial cells and fibroblasts in vitro. Collectively, our data provide an overview of molecular alterations that specifically occur in the cyst microenvironment and identify paracrine factors that may mediate early and advanced alterations in the cyst microenvironment.
2023-12-27 | GSE231304 | GEO
Project description:We show that resident macrophages accumulate in cilia mutant mice prior to cyst formation and that inhibition of resident macrophage accumulation reduces cystic kidney disease.
2019-07-04 | GSE131896 | GEO
Project description:The increased number of pancreatic cyst lesions (PCLs) have been detected through the development of abdominal imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS). However, accurate classification of cystic lesions is difficult because of the lack of standardized diagnostic methods, and thus potentially unnecessary surgical resection has been performed on pancreatic cyst patients. Among four most common types of cystic lesions of pancreas, intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCN), serous cystic neoplasms (SCN), and solid pseudopapillary neoplasms (SPNs), IPMNs, the precursor lesion of pancreatic cancer, have been detected most frequently, and are subdivided into low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive IPMN in accordance with their malignancy. To discover the potential biomarkers of the histological grades of IPMN, we investigated pancreatic cyst fluid proteins that are differentially expressed in accordance with the IPMN malignancy by LC-MS/MS analysis.
2020-09-06 | PXD016127 | Pride
Project description:Background The major gene mutated in autosomal dominant polycystic kidney disease was first identified over 20 years ago, yet its function remains poorly understood. We have used a systems-based approach to examine the effects of acquired loss of Pkd1 in adult mouse kidney as it transitions from normal to cystic state. Methods We performed transcriptional profiling of a large set of male and female kidneys, along with metabolomics and lipidomics analyses of a subset of male kidneys. We also assessed the effects of a modest diet change on cyst progression in young cystic mice. Fatty acid oxidation and glycolytic rates were measured in five control and mutant pairs of epithelial cells. Results We find that females have a significantly 46 less severe kidney phenotype and correlate this protection with differences in lipid metabolism. We show that sex is a major determinant of the transcriptional profile of mouse kidneys and that some of this difference is due to genes involved in lipid metabolism. Pkd1 mutant mice have transcriptional profiles consistent with changes in lipid metabolism and distinct metabolite and complex lipid profiles in kidneys. We also show that cells lacking Pkd1 have an intrinsic fatty acid oxidation defect and that manipulation of lipid content of mouse chow modifies cystic disease. Interpretation Our results suggest PKD could be a disease of altered cellular metabolism.
2016-01-26 | GSE72554 | GEO
Project description:Polycystic Kidney Disease is characterized by the formation of large fluid-filled cysts that eventually destroy the renal parenchyma leading to end-stage renal failure. Although remarkable progress has been made in understanding the pathologic mechanism of the disease, the precise orchestration of the early events leading to cyst formation is still unclear. Abnormal cellular proliferation was traditionally considered to be one of the primary irregularities leading to cyst initiation and growth. Consequently, many therapeutic interventions have focused on targeting this abnormal proliferation, and some have even progressed to clinical trials. However, the role of proliferation in cyst development was primarily examined at stages where cysts are already visible in the kidneys and therefore at later stages of disease development. In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0-60 days after birth) we performed gene expression profiling and phenotype analysis by measuring various kidney parameters. Phenotype analysis demonstrated that renal cysts appear immediately after birth in the PKD2 transgenic rat model (PKD2 (1-703)). On the other hand, abnormal proliferation occurs at later stages of the disease as identified by gene expression profiling. Interestingly, other pathways appear to be deregulated at early stages of the disease in this PKD model. Our data suggest that cystogenesis precedes deregulation of proliferation-related pathways, suggesting that proliferation abnormalities may contribute in cyst growth rather than cyst formation. In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0,6 and 24 days after birth) we performed gene expression profiling of kidney cells.
2010-01-31 | E-GEOD-19460 | biostudies-arrayexpress
Project description:Fumarate hydratase (FH) mutations predispose to renal cysts cancer. These cancers overexpress hypoxia-inducible factor-alpha (Hif-1a). We have generated a conditional Fh1 (mouse FH) knockout mice that develop renal cysts and overexpress Hif-1a. In order to identify the contribution of Hif-1a to cyst formation we have intercrossed our mice with conditional HIf-1a KO mice. We intercrossed Fh1/Hif1a mice with kidney specific cre recombinase (Ksp-Cre) and analysed kidney cyst formation. RNA was extracted from cysts from 4xFh1 KO, 4xFh1/Hif-1a KO and 4 control mice. For each comparison littermates were used and the animals were aged 15 weeks i.e. early cystic disease.
2011-10-23 | E-GEOD-29988 | biostudies-arrayexpress
Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Methods: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Results: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Conclusions: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways.
2021-07-15 | GSE179947 | GEO
Project description:Pilocytic astrocytoma is the most common type of brain tumor in pediatric population, generally connected with favorable prognosis, although recurrences or dissemination sometimes are also observed. For tumors originating in supra- or infratentorial location different molecular background was suggested but plausible correlations between transcriptional profile and radiological features and/or clinical course are still undefined. The purpose of this study was to identify gene expression profiles related to the most frequent locations of this tumor, subtypes based on various radiological features and clinical pattern of the disease. According to the radiological features presented on MRI, all cases were divided into four subtypes: solid or mainly solid, cystic with an enhancing cyst wall, cystic with a non-enhancing cyst wall and solid with central necrosis. Bioinformatic analyses showed that gene expression profile of pilocytic astrocytoma highly depends on the tumor location. Most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes expression which could distinguish pilocytic astrocytomas of different location even within supratentorial region. Analysis of the genes potentially associated between radiological features showed much weaker transcriptome differences. Single genes showed association with the tendency to progression. Here we showed that pilocytic astrocytomas of three different locations could be precisely differentiated on the basis of gene expression level but their transcriptional profiles did not strongly reflect the radiological appearance of the tumor or the course of the disease. Gene expression profiling was performed in 47 pilocytic astrocytoma tumours characterized by different localization, radiology and progression.
2015-10-30 | E-GEOD-73066 | biostudies-arrayexpress
Project description:Lipids play a crucial role in signalling and metabolism, regulating the development and maintenance of the skeleton. Membrane lipids have been hypothesised to act as intermediates upstream of orphan phosphatase 1 (PHOSPHO1), a major contributor to phosphate generation required for bone mineralisation. Here, we spatially resolve the lipid atlas of the healthy mouse knee and demonstrate the effects of PHOSPHO1 ablation on the growth plate lipidome. Lipids spanning 17 subclasses were mapped across the knee joints of healthy juvenile and adult mice using matrix-assisted laser desorption ionisation imaging mass spectrometry (MALDI-IMS), with annotation supported by shotgun lipidomics. Multivariate analysis identified 96 and 80 lipid ions with differential abundances across joint tissues in juvenile and adult mice respectively. In both ages, marrow was enriched in phospholipid platelet activating factors (PAFs) and related metabolites, cortical bone had a low lipid content, while lysophospholipids were strikingly enriched in the growth plate, an active site of mineralisation and PHOSPHO1 activity. Spatially-resolved profiling of PHOSPHO1-knockout (KO) mice across the resting, proliferating, and hypertrophic growth plate zones revealed 272, 306, and 296 significantly upregulated, and 155, 220 and 190 significantly downregulated features, respectively, relative to wild type (WT) controls. Of note, phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, lysophosphatidylethanolamine and phosphatidylethanolamine derived lipid ions were upregulated in PHOSPHO1-KO versus WT. Our imaging pipeline has established a spatially-resolved lipid signature of joint tissues and has demonstrated that PHOSPHO1 ablation significantly alters the growth plate lipidome, highlighting an essential role of the PHOSPHO1-mediated membrane phospholipid metabolism in lipid and bone homeostasis.
2023-04-19 | PXD038909 | Pride
Project description:The pancreatic cyst fluids were collected using a syringe aspiration of the cyst fluid immediately after surgical resection of the lesion. The cyst fluid were then aliquoted and stored in -80C freezer until ready to use. We plan on performing untargeted metabolomics analysis and unknown lipid analysis and identification on these pancreatic cyst fluid to find potential biomarkers that correlate with histopathological assessment and clinical behavior of these cystic lesions and thus to guide clinical management of patients. Abbreviations: IPMN - Intraductal Pancreatic Mucinous Neoplasm; MCN - mucinous cystic neoplasm; SCA - serous cystadenoma.
2017-07-14 | ST000823 | MetabolomicsWorkbench