Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformation - BVMC 6201
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PROVIDER: PRJNA511495 | ENA |
REPOSITORIES: ENA
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Project description:Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformation - BVMC 6201
| PRJNA511496 | ENA
Project description:Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with anendothelial cell-specific ablation of the Ccm3 gene (Ccm3iECKO), we show that endothelial cells from Ccm3iECKO mice have anincreased expression of inflammation-related genes.
2023-10-31 | GSE246373 | GEO
Project description:Cerebral cavernous malformations are vascular anomalies that can cause hemorrhagic stroke. Mutations in genes encoding Krit 1 (CCM1), OSM (CCM2), and PDCD10 (CCM3) proteins cause CCM. A loss in teh expression of any of these CCM proteins disrupts normal cerebral vessel development by disrupting the cytoskeleton and thereby inhibits endothelial tube ofrmation. Examination of cellular changes based on the loss of CCM gene expression may lead to the methods for early detection and prevention of CCM associated hemorrhagic stroke.
2014-06-09 | PXD000362 | Pride
Project description:Cerebral cavernous malformation (CCM) is a hemorrhagic neurovascular disease with no currently available therapeutics. Prior evidence suggests that different cell types may play a role in CCM pathogenesis. The contribution of each cell type to the dysfunctional cellular crosstalk remains unclear. Herein, RNA-seq was performed on FACS sorted endothelial cells (ECs), pericytes, neuroglia and microglia from CCM lesions and non-lesional brain tissue controls. Differentially Expressed Gene (DEG), pathway and Ligand-Receptor (LR) analyses were performed to characterize the dysfunctional genes of respective cell types within CCMs. Common DEGs among all three cell types were related to inflammation and endothelial-to-mesenchymal transition (EndMT). DEG and pathway analyses supported a role of lesional ECs in dysregulated angiogenesis and increased permeability. In addition, VEGFA was particularly upregulated in pericytes. Further pathway and LR analyses identified VEGFA/VEGFR2 signaling in lesional ECs and pericytes that would result in increased angiogenesis. Moreover, lesional pericytes and neuroglia predominantly showed DEGs and pathways mediating the immune response. Further analyses of cell specific gene alterations in CCM endorsed potential contribution to EndMT, coagulation, and a hypoxic microenvironment. Taken together, these findings motivate mechanistic hypotheses regarding non-endothelial contributions to lesion pathobiology and may lead to novel therapeutic targets.
2023-12-30 | GSE233210 | GEO
Project description:Comprehensive Transcriptome Analysis of Cerebral Cavernous Malformation Across Multiple Species and Genotypes
| PRJNA510400 | ENA
Project description:Purpose: To determine important genes, functions, and networks contributing to the pathobiology of cerebral cavernous malformation (CCM) from transcriptomic analyses across 3 species and 2 disease genotypes. Methods: Sequencing of RNA from laser microdissected neurovascular units (NVUs) of 5 human surgically resected CCM lesions, mouse brain microvascular ECs (BMECs) and C. elegans with induced Ccm gene loss, and their respective controls, provided differentially expressed genes (DEGs). DEGs from mouse and C. elegans were annotated into human homologous genes. Cross-comparisons of DEGs between species and genotypes as well as network and Gene Ontology (GO) enrichment analyses were performed. Results: Among hundreds of DEGs identified in each model, common genes and one GO term (GO:0051656 establishment of organelle localization) were commonly identified across the different species and genotypes. In addition, 24 GO functions were present in 4 out of 5 models and were related to cell-cell adhesion, neutrophil mediated immunity, ion transmembrane transporter activity, and responses to oxidative stress. We provide a comprehensive transcriptome library of CCM disease across species, and for the first time in Ccm1/Krit1 versus Ccm3/Pdcd10 genotypes Conclusion: We provide examples of how results can be used in hypothesis generation or mechanistic confirmatory studies.
2018-12-18 | GSE123968 | GEO
Project description:A cavernous hemangioma, well-known as vascular malformation, is present at birth, grows proportionately with the child, and does not undergo regression. Although a cavernous hemangioma has well-defined histopathological characteristics, its origin and formation remain unknown. In the present study, we characterized the cellular heterogeneity of cavernous hemangioma using single-cell RNA sequencing (scRNA-seq). The main contribution of the present study is the discovery of mesenchymal stem cells (MSCs) that cause cavernous hemangioma formation and may be abnormally or incompletely differentiated from epiblast stem cells. EGFR inhibitors are the potential drugs to treat cavernous hemangiomas. Other new findings include the responsive ACKR1 positive endothelial cell (ACKR1+EC) and BTNL9 positive endothelial cell (BTNL9+EC) and the BTNL9-caused checkpoint blockade enhanced by the CXCL12-CXCR4 signalling. The activated CD8+T and NK cells may highly express CCL5 for their infiltration in cavernous hemangiomas, independent on the tumor cell-derived CCL5-IFNG-CXCL9 pathway. The plasmacytoid dendritic cells (pDCs) function for anti-tumour as CD8+T cells in cavernous hemangiomas. The oxidised low-density lipoprotein (oxLDL) and scavenger receptors (SRs) may play an important role in the immune responses in the tumour microenvironment of cavernous hemangiomas. Notably, we propose that oxLDL induces the oxLDL-OLR1-NLRP3 pathway in M1-like macrophages via the over-expression of OLR1, whereas oxLDL induces the oxLDL-SRs-C1q pathway in M2-like macrophages via the over-expression of many SRs (LILRB5, etc) except OLR1. The highly expressed EREG in M1-like macrophages and the highly expressed EGFR in MSCs may cause MSC proliferation and the tumour progression. The present study revealed the origin of cavernous hemangiomas and reported the marker genes, cell types and molecular mechanisms, which are associated with the origin, formation, progression, diagnosis or therapy of cavernous hemangiomas. Our discoveries facilitate the development of gold standards for molecular diagnosis and effective drugs for treatment, and enrich the fundamental knowledge in the research field of immune, cancer and even cell biology.
2021-11-17 | GSE188515 | GEO
Project description:Patients with familial cerebral cavernous malformation (CCM) inherit germline loss of function mutations and are susceptible to progressive development of brain lesions and neurological sequelae during their lifetime. To date, no homologous circulat- ing molecules have been identified that can reflect the presence of germ line pathogenetic CCM mutations, either in animal models or patients. We hypothesize that homologous differentially expressed (DE) plasma miRNAs can reflect the CCM germline mutation in preclinical murine models and patients. Herein, homologous DE plasma miRNAs with mechanistic putative gene targets within the transcriptome of preclinical and human CCM lesions were identified. Several of these gene targets were additionally found to be associated with CCM-enriched pathways identified using the Kyoto Encyclopedia of Genes and Genomes. DE miRNAs were also identified in familial-CCM patients who developed new brain lesions within the year following blood sample collection. The miRNome results were then validated in an independent cohort of human subjects with real-time-qPCR quantification, a technique facilitating plasma assays. Finally, a Bayesian-informed machine learning approach showed that a combination of plasma levels of miRNAs and circulating proteins improves the associa- tion with familial-CCM disease in human subjects to 95% accuracy. These findings act as an important proof of concept for the future development of translatable circulating biomarkers to be tested in preclinical studies and human trials aimed at monitoring and restoring gene function in CCM and other diseases.
2023-05-09 | GSE232008 | GEO
Project description:Patients with familial cerebral cavernous malformation (CCM) inherit germline loss of function mutations and are susceptible to progressive development of brain lesions and neurological sequelae during their lifetime. To date, no homologous circulat- ing molecules have been identified that can reflect the presence of germ line pathogenetic CCM mutations, either in animal models or patients. We hypothesize that homologous differentially expressed (DE) plasma miRNAs can reflect the CCM germline mutation in preclinical murine models and patients. Herein, homologous DE plasma miRNAs with mechanistic putative gene targets within the transcriptome of preclinical and human CCM lesions were identified. Several of these gene targets were additionally found to be associated with CCM-enriched pathways identified using the Kyoto Encyclopedia of Genes and Genomes. DE miRNAs were also identified in familial-CCM patients who developed new brain lesions within the year following blood sample collection. The miRNome results were then validated in an independent cohort of human subjects with real-time-qPCR quantification, a technique facilitating plasma assays. Finally, a Bayesian-informed machine learning approach showed that a combination of plasma levels of miRNAs and circulating proteins improves the associa- tion with familial-CCM disease in human subjects to 95% accuracy. These findings act as an important proof of concept for the future development of translatable circulating biomarkers to be tested in preclinical studies and human trials aimed at monitoring and restoring gene function in CCM and other diseases.
2023-05-09 | GSE232009 | GEO
Project description:Bulk RNA-seq analysis of HUVEC cell cultures with Cerebral Cavernous Malformation (CCM) protein knockdown
| PRJNA478141 | ENA