Project description:Patients with epilepsy often experience increased frequency of seizures at night. Given the crucial role glial cells play in modulating neuronal excitability, we hypothesize that circadian changes in glia may affect changes in seizure threshold. Fatty acid binding protein 7 (Fabp7) is expressed in brain astrocytes and is involved in the transport of fatty acids, signal transduction, and gene transcription. Its mRNA expression levels rise and fall in a circadian rhythm and is necessary for normal sleep regulation. We examined if Fabp7 influences electrically induced seizure threshold and differential gene expression in wild type (WT) vs. Fabp7 knockout (KO) mice with and without seizure.
Project description:To discover the molecules and signal pathways that are associated with the anti-aging effects of Fabp7 deficiency, transcriptome analyses were conducted using DNA microarray. The ABR thresholds of Fabp7 (+/+) and Fabp7 (-/-) mice were not significantly different at 7 months of age, but it was speculated that important gene expression changes might arise at approximately this stage. Therefore, 7-month-old Fabp7 (+/+) and Fabp7 (-/-) mice were used for transcriptome analyses.
Project description:We demonstrated that Wnt/β-catenin pathway was activated in in endotoxemic mice, and the modulation of this pathway by LGK974 had beneficial effects by suppressing the inflammation and lethality caused by endotoxemia.
Project description:Endotoxemia is a key feature of sepsis pathogenesis and has also been found to mediate the pathophysiology of multiple chronic inflammatory conditions. In this work, we expand upon a model of endotoxemia due to lipopolysaccharide (LPS) using zebrafish and demonstrate that this model displays activation of inflammatory and pro-coagulant genes, impaired coagulation in response to endothelial injury, and signs of organ dysfunction. An in silico analysis revealed that there were multiple associations between the RNA-seq signature of LPS treated embryos and the RNA-seq signature of genes and drugs involving diverse pathways. An in vivo screen involving >1,500 FDA approved drugs identified multiple compounds spanning several drug categories that partially or completely prevented endotoxemic death. Three small molecules including one anticoagulant dabigatran were identified through both the in vivo and in silico analyses. Dabigatran, a direct thrombin inhibitor, significantly reduced the upregulation of inflammatory cytokines and pro-coagulant genes and completely protected zebrafish from endotoxemic death due to LPS. However, other anticoagulants argatroban (direct thrombin inhibitor), and rivaroxaban and apixaban, (factor Xa inhibitors), conferred no such protection. Lastly, prothrombin mutant fish displayed no increase in survival when treated with LPS. These data together suggest that dabigatran protects zebrafish from endotoxemia through a mechanism independent of its anticoagulant effect. In summary, our in silico and in vivo analyses reveals that dabigatran and several other novel small molecules prevent LPS induced endotoxemia and warrant further therapeutic exploration in inflammatory conditions, both acute and chronic.
Project description:Liver has a crucial role in the regulation of immune defense in systemic infections. During endotoxemia, the liver transits from an immune-tolerant towards an immune-active state and forms the first line of defense against invading microorganisms. the role of liver nonparenchymal cells in endotoxemia remains unintelligible. To characterize the liver nonparenchymal cells in endotoxemia liver, we performed single-cell RNA sequencing of liver nonparenchymal cells from healthy C57BL/6J mice and murine model of endotoxemia at early or late stage. The single-cell RNA-seq analyses revealed the heterogeneity of liver nonparenchymal cells in endotoxemia liver.
Project description:Liver has a crucial role in the regulation of immune defense in systemic infections. During endotoxemia, the liver transits from an immune-tolerant towards an immune-active state and forms the first line of defense against invading microorganisms. the role of liver parenchymal cells in endotoxemia remains unintelligible. To characterize the liver parenchymal cells in endotoxemia liver, we performed single-cell RNA sequencing of liver parenchymal cells from healthy C57BL/6J mice and murine model of endotoxemia at early or late stage. The single-cell RNA-seq analyses revealed the heterogeneity of liver parenchymal cells in endotoxemia liver.