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ABSTRACT:
PROVIDER: PRJDB20079 | ENA |
REPOSITORIES: ENA
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Project description:Rationale: The acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease’s complex pathophysiology, yet these cells have been little studied. Objectives: To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared to healthy volunteer cells, and define their sensitivity to phosphoinositide 3-kinase inhibition. Methods: Twenty three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis and adhesion molecules were quantified by flow cytometry, and oxidase responses by chemiluminescence. Cytokine and transcriptional profiling utilized multiplex and GeneChip arrays. Measurements and Main Results: Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed apoptosis and constitutively primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the pro-survival phenotype of patient cells was recalcitrant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal and cell death pathways in patient cells, aligning closely to sepsis and burns data sets but not with phosphoinositide 3-kinase signatures. Conclusions: Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed, pro-survival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent, but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells.
2016-04-11 | GSE76293 | GEO
Project description:<p>The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.</p>
| phs000341 | dbGaP
Project description:Cardiac hypertrophy can lead to heart failure, and is induced either by physiological stimuli eg postnatal development, chronic exrcise training or pathological stimuli eg pressure or volume overload. This data set looks at microRNA profiles in mouse models to examine whether phosphoinositide 3-kinase (p110 alpha isoform) activity is critical for the maintenance of cardiac function and long term survival in a seeting of heart failure (myocardial infarction). The significance and expected outcome are to recognise genes involved in models of heart failure and attempt to examine underlying regulator pathways involved in possible cardica maintenance in the PI3K mouse model. The matching mRNA gene expression profile (GSE7487) is examined to look for mRNA and microRNA interactions. miRNA expression correlates directly with cardiac function. PI3K regulon ameliorates cardiac stress. Keywords: microRNA profiling, regulatory pathway discovery, genotype comparison
2010-03-08 | GSE14267 | GEO
Project description:Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrial-targeted nuclear genes in concert with reduced signaling via PPARα/PGC-1α and other transcriptional regulators. In cultured myocytes Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO, but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity. Three samples per group of 8-week-old wild-type or transgenic mice with cardiac-specific constitutive expression of an activated Akt (caAkt) in the heart at 8 weeks of age were used. Mice have been previously described in depth (Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, Cantley LC, Izumo S. 2002. Akt/protein kinase B promotes organ growth in transgenic mice. Mol. Cell. Biol. 22:2799-2809.). After hearts were removed total myocardial RNA was labeled and processed as described below for microarray analysis to detail the global changes in gene expression underlying development of heart failure in this mouse model.
2015-01-05 | E-GEOD-63848 | biostudies-arrayexpress
Project description:Trained immunity and immune tolerance have been identified as long-term response patterns of the innate immune system. The causes of these opposing reactions remain elusive. Here we report about differential inflammatory responses of microglial cells derived from neonatal mouse brain to increasing doses of the endotoxin LPS. Prolonged priming with ultra-low LPS doses provokes trained immunity, i.e. increased production of pro-inflammatory mediators in comparison to the unprimed control. In contrast, priming with high doses of LPS induces immune tolerance implying decreased production of inflammatory mediators and pronounced release of anti-inflammatory cytokines. Investigation of the signaling processes and cell functions involved in these memory-like immune responses reveals essential role of phosphoinositide 3-kinase γ (PI3Kγ), one of the phosphoinositide 3-kinase species highly expressed in innate immune cells. Together, our data suggest profound influence of preceding contacts with pathogens on the immune response of microglia. The impact of these interactions – trained immunity or immune tolerance - appears to be shaped by pathogen dose.
2019-12-05 | GSE137741 | GEO
Project description:Tight regulation of hematopoietic stem cell (HSC) homeostasis is essential for life-long hematopoiesis, for preventing blood cancers and for averting bone marrow failure. The underlying mechanisms are incompletely understood. Here, we identify production of inositol-tetrakisphosphate (IP4) by inositoltrisphosphate 3-kinase B (ItpkB) as essential for HSC quiescence and function. Young ItpkB-/- mice accumulated phenotypic HSC and showed extramedullary hematopoiesis. ItpkB-/- HSC were less quiescent and proliferated more than wildtype controls. They downregulated quiescence and stemness associated mRNAs, but upregulated activation, oxidative metabolism, protein synthesis and lineage associated transcripts. Although they showed no significant homing defects, ItpkB-/- HSC had a severely reduced competitive long-term repopulating potential. Aging ItpkB-/- mice lost hematopoietic stem and progenitor cells and died with severe anemia. Wildtype HSC normally repopulated ItpkB-/- hosts, incidating a HSC-intrinsic ItpkB requirement. ItpkB-/- HSC had reduced cobblestone-area forming cell activity in vitro and showed increased stem-cell-factor activation of the phosphoinositide 3-kinase (PI3K) effector Akt, reversed by exogenous provision of the known PI3K/Akt antagonist IP4. They also showed transcriptome changes consistent with hyperactive Akt/mTOR signaling. Thus, we propose that ItpkB ensures HSC quiescence by limiting cytokine-induced PI3K signaling in HSC.
2015-03-31 | GSE56613 | GEO
Project description:T helper (Th) cell differentiation is driven by antigen and accessory signals that activate phosphoinositide 3-kinase (PI3K) to induce transcriptional and metabolic reprogramming including aerobic glycolysis (the Warburg effect). Here, we show that ATP generated through glycolysis fuels PI3K signaling to promote pathogenic Th17 cell responses. Mice with T cell-specific ablation of the glycolytic enzyme lactate dehydrogenase A (LDHA) were resistant to Th17 cell-mediated experimental autoimmune encephalomyelitis in association with defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled the cellular redox balance and inhibited ATP production causing attenuated phosphoinositide (3,4,5)-trisphosphate generation, and diminished activation of the Akt kinase and phosphorylation of its transcription factor target Foxo1. Th17 cell-specific expression of an Akt-insensitive Foxo1 mutant recapitulated the Th17 cell differentiation defects caused by LDHA deficiency. Thus, PI3K signaling and glycolytic bioenergetics constitute a positive feedback regulatory circuit essential for Th17 cell-mediated autoimmunity.
2021-03-27 | GSE164959 | GEO
Project description:Transcriptional profile of cardiac aging and its modification by insulin signaling (CBX72)
| PRJDB20049 | ENA
Project description:Investigation of transcriptional profile of clpX deleion mutant in Klebsiella pneumoniae (CBX130)
| PRJDB20096 | ENA
Project description:Memory encodes past experiences, thereby enabling future plans. The basolateral amygdala (BLA) is a center of salience networks that underlie emotional experiences and thus plays a key role in long-term fear memory formation. Here we used single-cell transcriptomics to illuminate the cellular and molecular architecture of the role of the basolateral amygdala in long-term memory. We identified transcriptional signatures in subpopulations of neurons and astrocytes that were memory-specific and persisted for weeks. These transcriptional signatures implicate neuropeptide and brain-derived neurotrophic factor (BDNF) signaling, mitogen-activated protein kinase (MAPK) and cAMP response element-binding protein (CREB) activation, ubiquitination pathways, and synaptic connectivity as key components of long-term memory. Strikingly, upon long-term memory formation a neuronal sub-population defined by increased Penk and decreased Tac expression constituted the most prominent component of the BLA’s memory engram.
2023-10-26 | GSE246147 | GEO