Gene expression profile of endothelial cells in a 3D-casted mold of a human aneurysm.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE217440 | GEO | 2022/11/12
REPOSITORIES: GEO
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Project description:Background and Purpose: We previously showed that intracranial aneurysm (IA)-associated single nucleotide polymorphisms (SNPs) are enriched in promoters and putative enhancers of the human circle of Willis (CoW), on which IAs develop, suggesting a role for such regulatory regions in IA. In this study we further investigated the role of these putative enhancers in the pathogenesis of IA by identifying the target genes of these enhancers and validating their regulatory activity. Methods: We selected putative enhancers in IA-associated regions from genome wide association studies, using our previously published CoW chromatin immunoprecipitation and sequencing data. Next, we used a chromatin conformation capture technique (4C) to identify physical interactions between these putative enhancers and the promoters of their target genes. Subsequently, we assessed the activity of the identified enhancers in vivo in zebrafish embryos and we analyzed gene expression of the target genes identified with 4C in CoW RNA-sequencing data and by in situ hybridization on CoW paraffin sections. Results: We identified fifteen enhancers that interact with the promoters of six target genes: SOX17, CDKN2B, MTAP, CNNM2, RPEL1 and GATA6. For eight out of eleven enhancers that could be tested, we confirmed in vivo activity in the zebrafish embryos. These eight enhancers reside in four out of six IA-associated GWAS regions. All six target genes are expressed in the CoW and in situ hybrdization showed that these genes are expressed in multiple cell types in the CoW. Conclusions: In four out of six IA-associated GWAS regions we identified eight enhancers that are active in vivo and interact with six nearby genes, suggesting that these genes are regulated by the identified enhancers. These genes, SOX17, CDKN2B, MTAP, CNNM2, RPEL1 and GATA6, are potential candidate genes involved in IA pathogenesis and should be studied using animal models in the future.
2019-04-27 | GSE115304 | GEO
Project description:To investigate the role of smoking in the rupture of intracranial aneurysms (IA), plasma miRNA profiles of smoking IA patients, non-smoking IA patients, and healthy volunteers were analyzed.
2023-11-15 | GSE231922 | GEO
Project description:Rupture of intracranial aneurysms (IAs) leads to subarachnoid hemorrhage (SAH), a sudden-onset disease often causing severe disability or death. Using whole exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4 in both index and familial IA cases. Ppil4 depletion causes intracerebral hemorrhage, defects in cerebrovascular morphology, and impaired Wnt signaling in vivo. Wild type, but not IA-mutant PPIL4, potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity, and implicate PPIL4 gene variation in the pathogenesis of human IA.
| EGAS00001005518 | EGA
Project description:Background and Purpose: Genome-wide association studies significantly link intracranial aneurysm (IA) to single-nucleotide polymorphisms (SNPs) in six genomic loci. To gain insight into the relevance of these IA associated SNPs, we aimed to identify regulatory regions and analyze overall gene expression in the human circle of Willis (CoW), on which these aneurysms develop. Methods: We performed chromatin immunoprecipitation and sequencing for histone modifications H3K4me1 and H3K27ac to identify regulatory regions, including distal enhancers and active promoters, in post mortem specimens of the human CoW. These experiments were complemented with RNA sequencing on the same specimens. We determined whether these regulatory regions overlap with IA associated SNPs, using computational methods. By combining our results with publicly available data, we investigated the effect of IA associated SNPs on the newly identified regulatory regions and linked them to potential target genes. Results: We find that IA associated SNPs are significantly enriched in CoW regulatory regions. Some of the IA associated SNPs that overlap with a regulatory region are likely to alter transcription factor binding, and in proximity to these regulatory regions are 102 genes that are expressed in the CoW. In addition, gene expression in the CoW is enriched for genes related to cell adhesion and the extracellular matrix. Conclusions: CoW regulatory regions link IA associated SNPs to genes with a potential role in the development of IAs. Our data refine previous predictions on SNPs associated with IA and provide a substantial resource from which candidates for follow-up studies can be prioritized.
2018-01-04 | GSE107196 | GEO
Project description:Intracranial aneurysm (IA) is a pathological dilation of the cerebral artery which has a potential to rupture leading to sub arachnoid haemorrhage (SAH). One third of the patients with aneurysmal SAH (aSAH) develop symptomatic narrowing of the blood vessels called cerebral vasospasm. The outcomes in the above clinical scenarios are variable and devastating. The study was designed to decipher the molecular mechanisms underlying the pathophysiology of intracranial aneurysm formation, its rupture and subsequent development of vasospasm at the proteomic level. The study was done in two phases – discovery phase and validation phase. We performed iTRAQ-based quantitative proteomic analysis of brain vessel tissue and serum samples in three subgroups of patients with IA and compared them with those of control group (subjects with no cerebrovascular disorder) during the discovery phase. In validation phase, dysregulated proteins of biological significance i.e. ORM1 as a biomarker for unruptured aneurysm and MMP9 as a biomarker for cerebral vasospasm were validated in larger cohort of patients.
2022-09-07 | PXD013442 | Pride
Project description:The introduction of poly(dimethylsiloxane) (PDMS) and soft lithography in the 90's has revolutionized the field of microfluidics by almost eliminating the need for a clean-room environment for device fabrication. More recently, 3D printing has been introduced to fabricate molds for soft lithography, the only step for which a clean-room environment is still often necessary, to further support the rapid prototyping of PDMS microfluidic devices. However, toxicity of most of the commercial 3D printing resins has been established, and little is known regarding the potential for 3D printed molds to leak components into the PDMS that would, in turn, hamper cells and/or tissues cultured in the devices. In the present study, we investigated if 3D printed molds produced by stereolithography can leach components into PDMS, and compared 3D printed molds to their more conventional SU-8 counterparts. Different leachates were detected in aqueous solutions incubated in the resulting PDMS devices prepared from widely used PDMS pre-polymer:curing agent ratios (10:1, 15:1 and 20:1), and these leachates were identified as originating from resins and catalyst substances. Next, we explored the possibility to culture cells and tissues in these PDMS devices produced from 3D printed molds and after proper device washing and conditioning. Importantly, we demonstrated that the resulting PDMS devices supported physiological cultures of HeLa cells and ovarian tissues in vitro, with superior outcomes than static conventional cultures.
| S-EPMC6976631 | biostudies-literature
Project description:Tumors engender an environment dominated by M2 differentiated tumor macrophages that support tumor invasion, metastases and escape from immune control. In this study, we demonstrate that following radiation therapy of tumors in mice there is an influx of tumor macrophages that polarize towards wound repair and immune suppression. To investigate changes in the phenotype of tumor macrophages following radiation therapy, we FACS sorted tumor macrophages from Panc02 tumors. We have previously shown that we can distinguish mature tumor macrophages from immature myeloid and MDSC populations by expression of Gr1 and IA (MHC class II). To isolate these sub-populations, we first gated CD11b+ cells in the untreated or irradiated tumors, then sorted the CD11b+IA+ macrophage population and the CD11b+Gr1hi MDSC population. Cytospins of the sorted populations demonstrates that the CD11b+Gr1hi MDSC predominantly have a granulocyte morphology and the CD11b+IA+ cells have a macrophage morphology in both the untreated and irradiated tumors. RNA was purified from CD11b+IA+ macrophages from untreated or irradiated tumors 1 day or 7 days following radiation therapy and Gene Expression Microarray analysis was performed.
2011-12-07 | GSE34206 | GEO
Project description:The aim of the project is to identify the genes in megakaryocytes whose expression is modified upon 3D methylcellulose hydrogel culture compared to liquid culture. Megakaryocytes are the precursor cells of platelets. We previously showed that growing megakaryocytes in 3D hydrogel strongly modifies their differentiation and their morphology, being closer to the one in situ. We were thus interested into identifying these mechanobiological pathways induced by the confinement. We found that 3D culture notably upregulated genes related to the Rho GTPase pathway.
2024-08-20 | GSE264159 | GEO
Project description:<p>Our long-term objective is to identify susceptibility genes that are related to the formation of intracranial aneurysms (IA). Rupture of IAs occurs in 16,000 to 17,000 persons in the U.S. annually and nearly half of affected persons are dead within the first 30 days. An additional 6,000 to 7,000 persons with unruptured IAs are identified each year. Accumulated evidence indicates that a genetic component plays an important role in the development of IAs, but specific loci affecting the risk of IA have not been identified. The primary hypothesis of this study is that there are specific human chromosomal regions that are associated with an increased risk of IAs. Specific Aims of are: <ol> <li>Recruitment of 400 (475) families with multiple individuals who have an IA through 23 (25) referral centers throughout North America, Australia, and New Zealand that represent 35 (40) recruitment sites.</li> <li>Ascertainment of interviews and blood samples from all affected family members as well as their first-degree relatives. White blood cells from living persons with an IA will be cryopreserved at Coriell Institute for Medical Research for future immortalization of cells lines as indicated.</li> <li>Identification of unruptured IAs by obtaining MRAs in selected asymptomatic siblings (of affected individuals).</li> <li>Completion of a 10 cM genome series in persons with IAs as well as the spouses and children of persons with an IA who are deceased. We will perform finer mapping of chromosomal regions with suggestive evidence of linkage in the genome screen.</li> <li>Performance of a nonparametric (allele sharing) linkage analysis, including relevant environmental factors such as smoking, to identify chromosomal regions linked to IA. Reconstruction of the genotypes of deceased affected family members will be performed.</li> </ol> </p> <p>Identification of individuals who are genetically at high risk for the development of IAs would enable targeted and effective screening/prevention/treatment strategies to reduce the substantial mortality and morbidity associated with this devastating type of stroke. Only a multidisciplinary, collaborative effort to identify, accrue, and genotype FIA families will be successful in identifying sufficient high-risk families to characterize the genetic underpinnings of IA.</p>
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Project description:Tumors engender an environment dominated by M2 differentiated tumor macrophages that support tumor invasion, metastases and escape from immune control. In this study, we demonstrate that following radiation therapy of tumors in mice there is an influx of tumor macrophages that polarize towards wound repair and immune suppression. To investigate changes in the phenotype of tumor macrophages following radiation therapy, we FACS sorted tumor macrophages from Panc02 tumors. We have previously shown that we can distinguish mature tumor macrophages from immature myeloid and MDSC populations by expression of Gr1 and IA (MHC class II). To isolate these sub-populations, we first gated CD11b+ cells in the untreated or irradiated tumors, then sorted the CD11b+IA+ macrophage population and the CD11b+Gr1hi MDSC population. Cytospins of the sorted populations demonstrates that the CD11b+Gr1hi MDSC predominantly have a granulocyte morphology and the CD11b+IA+ cells have a macrophage morphology in both the untreated and irradiated tumors. RNA was purified from CD11b+IA+ macrophages from untreated or irradiated tumors 1 day or 7 days following radiation therapy and Gene Expression Microarray analysis was performed. There are untreated and irradiated samples at time points 1 day and 7 days following radiation therapy. The experiment was repeated in entirety, generating a second gene array sample for each. For analysis, the untreated samples of 1 day and 7 days were grouped together.
2011-12-07 | E-GEOD-34206 | biostudies-arrayexpress