Spatial transcriptomics for intrathoracic adhesion in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE308260 | GEO | 2026/04/09
REPOSITORIES: GEO
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Project description:We established a novel mouse model of intrathoracic adhesions (IA) to investigate the molecular mechanisms underlying IA formation. RNA sequencing analysis was performed to explore these mechanisms. A 200 μL talc solution was administered into the left thoracic cavity, and the mice were sacrificed at 30 minutes, 3 days, and 9 days post-administration. IA tissues, including the left lung parenchyma and chest wall, were harvested and homogenized using QIAzol lysis reagent. Total RNA was extracted, and the FASTQ file data were trimmed and mapped using the GLC Genomics Workbench. Differential gene expression and enrichment analyses were performed using RNAseq Chef version 1.1.2. According to the bulk RNA analysis, we observed a significant upregulation of genes associated with inflammatory cytokines and macrophage surface markers, including Il6, Ccl2, Il1β, Tgfβ1, Cd163, Cd68, and Cd86, at day 3. Meanwhile, genes related to the extracellular matrix (ECM) and its production processes were significantly upregulated at day 9. Cnet plot showed that the TNF-α and NF-κB signaling pathways were activated during the early phase, while epithelial-mesenchymal transition occurred during the completion phase of IA formation. Ingenuity Pathway Analysis (IPA) on day 3 revealed activation of leukocyte trafficking, maturation, and emigration, along with agranulocyte adhesion and diapedesis.
2026-04-09 | GSE284182 | GEO
Project description:The rupture of intracranial aneurysm (IA) causes subarachnoid hemorrhage associated with high morbidity and mortality. We compared gene expression profiles in aneurysmal domes between unruptured IAs (UIAs) and ruptured IAs (RIAs) to elucidate biological mechanisms predisposing to the rupture of IA. We determined gene expression levels of eight RIAs, five UIAs, and 10 superficial temporal arteries (STAs) with the Agilent microarrays. To explore biological heterogeneity of IAs, we classified the samples into subgroups showing similar gene expression patterns by using clustering methods. The clustering analysis identified four groups: STAs and UIAs were aggregated their own clusters, whereas RIAs segregated into two distinct subgroups (early and late RIAs). By comparing gene expression levels between early RIAs and UIAs, we identified 430 up-regulated and 617 down-regulated genes in early RIAs. The up-regulated genes were associated with inflammatory and immune responses and phagocytosis including S100/calgranulin genes (S100A8, S100A9, and S100A12). The down-regulated genes suggest mechanical weakness of aneurysm walls. The expressions of Krüppel-like family of transcription factors (KLF2, KLF12, and KLF15), which were anti-inflammatory regulators, and CDKN2A, which was located on chromosome 9p21 that was the most consistently replicated locus in genome-wide association studies of IA, were also down-regulated. We demonstrate that gene expression patterns of RIAs were different according to age of the patients. The results suggest that macrophage-mediated inflammation is a key biological pathway for IA rupture. The identified genes can be good candidates for molecular markers of rupture-prone IAs and therapeutic targets.
2014-07-14 | GSE54083 | GEO
Project description:The purpose of the present study was to investigate the activation of the cardiac inflammatory response in the hearts of SHAM (surgical opening of the chest) mice in comparison to CONTROL hearts isolated from naïve (not operated) mice. Male C57BL/6J (10 weeks) were subjected to an open-chest ischemia-reperfusion (I/R) SHAM procedure in order to examine the effects of this surgery alone in producing cardiac inflammation. The procedure consisted of thoracotomy and a suture passed around the left anterior descending artery (LAD). The mouse chest was kept open for approximately 45 min. We chose to study an open-chest I/R SHAM because this is the reference surgery for the most common surgical procedure used to study cardiac inflammation. Mice were sacrificed 5 days after the procedure and the hearts were removed and used in RNAseq experiments.
2020-10-04 | GSE120867 | GEO
Project description:Background: Late-onset Alzheimer´s disease (LOAD) is a heterogeneous disorder influenced by complex genetic factors. We previously described intermediate alleles (IAs; 27-35 CAG repeats) in the huntingtin (HTT) gene as potential modifiers in around 6% of AD population. The caudate nucleus, the most affected region in Huntington's disease, is highly sensitive to these HTT CAG repeats. We hypothesized that HTT IAs induce gene expression deregulation, including altered microRNA (miRNA) profiles, leading to altered disease progression. Methods: We investigated the impact of HTT IAs on LOAD progression by genotyping HTT CAG repeats in a cohort of 323 LOAD patients and 335 healthy controls. Comprehensive histopathological and molecular analyses were performed on caudate nucleus samples from a matched subcohort (6 healthy controls, 14 LOAD non-HTT IA carriers, and 13 LOAD HTT IA carriers). Results: HTT IAs carriers patients exhibited decreased survival after disease onset compared to non-carriers. Histopathologically, while LOAD patients showed increased soluble HTT levels and altered tau pathology compared to controls, these changes were consistently and markedly exacerbated in HTT IA carriers. This phenotype was characterized by heightened diffuse HTT immunoreactivity and an advanced maturation of tau pathology, specifically a pronounced increase in neuronal tau 3R burden and 3R tau-enriched ghost tangles. Interestingly, this pathological state was associated with alterations in key splicing factors, including decreased SRSF6 levels and increased nuclear FUS-SFPQ complex assembly. Analysis of microRNA (miRNA) profiling in the caudate nucleus revealed that the LOAD-associated miRNA dysregulation was significantly amplified in HTT IA carriers, identifying a signature of five miRNAs (miR-100-5p, miR-218-5p, miR-27b-3p, miR-487-3p, and miR-9-3p). In silico modeling and target validation demonstrated that these miRNAs target components of the nuclear spliceosome machinery, such as SRSF family, along with MAPT and HTT genes, suggesting a direct link to the observed tauopathy. Conclusions: Our findings underscore that HTT IAs as critical modifiers in LOAD progression through an miRNA-mediated dysregulation of splicing and proteostasis. Thus, identifying HTT IAs through routine blood genetic screening offers a practical, non-invasive biomarker for patient stratification, taking a step forward to personalized therapeutic strategies in LOAD.
2026-03-07 | GSE300433 | GEO
Project description:Subarachnoid hemorrhage due to rupture of intracranial aneurysm (IA) still has poor prognosis once after the onset in spite of modern technical advancement in medical care. The development of the novel therapeutic strategy based on molecular machineries regulating the rupture is thus mandatory for social health. Here, recent studies have clarified the potential role of neutrophil-mediated inflammatory responses in the process leading to rupture. Thereby, factors mediating the recruitment of neutrophils in situ could be the therapeutic targets to prevent rupture of IAs. In the present study, complement C5a receptor 1 (C5AR1) was picked up as the candidates from comprehensive gene expression profile data. The induction of C5AR1 in IA lesions exclusively in rupture-prone or ruptured lesions was then confirmed in immunohistochemistry. The ligand of C5AR1, C5a, was induced through the enzymatic digestion by tissue-type Plasminogen Activator and, intriguingly, forms the auto-amplification in C5a-C5AR1 axis to exacerbate neutrophil infiltration and resultant neutrophil-mediated inflammation in situ, which triggers rupture of IAs. In conclusion, we have, in the present study, examined potential factors mediating the infiltration of neutrophils into IA lesions and then identified C5a-C5AR1 axis. This cascade could become the therapeutic target to prevent rupture of IAs.
2025-09-08 | GSE242795 | 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>
| phs000293 | dbGaP
Project description:<p>Intracranial aneurysms (IAs) are benign cerebrovascular maladies characterized by pathological dilatation in the walls of intracranial arteries. However, spontaneous subarachnoid hemorrhage (SAH) resulting from aneurysm rupture poses a grave threat to the patient's life. Accumulating evidence implicates gut ecological dysregulation in the pathogenesis of IAs. Nevertheless, the relevance of gut dysbiosis to the rupture of IAs remains unknown. In this study, altogether 124 fecal samples were employed for microbiome sequencing by third-generation 16s rRNA sequencing, while 160 fecal samples were sequenced for metabolomics sequencing by liquid chromatography-mass spectroscopy techniques. Furthermore, the stool samples from IAs and healthy family controls were partitioned into two cohorts: the discovery set and the validation set for mutual cross-validation. Differential gut microbiota and metabolites associated with ruptured intracranial aneurysms (RIAs) were identified. Additionally, a superior risk assessment model for RIAs was constructed utilizing these differential species and metabolites. Subsequent integrated metabolomics and microbiomics analyses have uncovered a profound link between the dysregulation of unsaturated fatty acid and essential amino acid metabolic pathways and the rupture of IAs. This metabolic imbalance is attributed to alternations in the gut microbiota composition. Furthermore, we further revealed alterations in the gut flora of patients with IAs at high-risk rupture locations, incorporating the clinical characteristics. Finally, 30 peripheral blood and paired cerebrospinal fluid samples were tested to confirm variations in α-linolenic acid, linoleic acid and butyric acid concentrations among IA patients. This study underscores the crucial role of gut microbiota and metabolisms dysbiosis in IAs formation, while also highlighting a novel risk factor for aneurysm rupture. The identification and validation of differential species and metabolites provide new assessment biomarkers against IAs rupture.</p>
2024-12-13 | MTBLS10263 | MetaboLights
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>
| phs000293.v1.p1 | EGA
Project description:Rupture of intracranial aneurysms (IAs) represents a life-threatening cerebrovascular event associated with high morbidity and mortality. Elucidating the pathological mechanisms driving IA initiation and progression is critical for developing an effective therapeutic strategy. Endothelial cell (EC) dysfunction is known to contribute to IA pathogenesis. Hemodynamic force— particularly fluid shear stress (FSS) are well-established mediators of IA pathogenesis, yet the mechanisms by which FSS triggers endothelial injury remain incompletely understood. In this study, single-cell sequencing of human revealed that endothelial-to-mesenchymal transition (EndMT) as a hallmark feature of early-stage IA formation, whereas EndMT was markedly attenuated in ruptured aneurysms. Using a mouse IA model and an in vitro parallel-plate flow chamber system, we demonstrated that exposure to high laminar FSS (HSS) promotes EndMT in endothelial cells, concomitant with actin cytoskeletal reorganization and nuclear translocation of Yes-associated protein (YAP). In contrast, under low or vortex flow (VSS) conditions characteristic of advanced IA stages, endothelial cells undergo phenotypic reversion—evidenced by reduced expression of cytoskeletal proteins and cytoplasmic sequestration of YAP. Notably, endothelial inflammation escalates progressively throughout IA development and contributes directly to sustained endothelial dysfunction. Pharmacological inhibition of actin polymerization effectively suppressed EndMT in the early stage but failed to restore endothelial integrity during the late stage. Collectively, these findings identify FSS–cytoskeleton–YAP–EndMT axis as a stage-specific, druggable pathway with translational potential for early intervention in intracranial aneurysm disease.
2026-05-05 | GSE329653 | GEO
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