Project description:Olfactory dysfunction is an underestimated symptom in multiple sclerosis (MS). Here, we examined the pathogenic mechanisms underlying inflammation-induced dysfunction of the olfactory bulb using the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Reduced olfactory function in EAE was associated with the degeneration of short-axon neurons, immature neurons, and mitral cells, together with their synaptic interactions and axonal repertoire. To dissect the mechanisms underlying the susceptibility of mitral cells, the main projection neurons of the olfactory bulb, we profiled their responses to neuroinflammation by single-nucleus RNA sequencing. Neuroinflammation resulted in the induction of potassium channel transcripts in mitral cells, which was reflected in reduced halothane-induced outward currents of these cells, likely contributing to the impaired olfaction in EAE animals.
Project description:Mitral cells in the mouse olfactory bulb are known to remodel their primary dendrites and form lateral dendrites during postnatal development. These processes are suppressed when neuronal activity is silenced by overexpression of Kir2.1 in mitral cells, indicating that neuronal activity in mitral cells is required. However, it is unclear what changes in gene expression lead to the remodeling of mitral cell dendrites in an activity-dependent manner. To address this, we performed a microarray-based analysis of gene expression in mitral cells during normal development and under the activity-silenced condition.
Project description:It is important to maintain cognitive integrity during underwater operations, which may also trigger cognitive alterations. Cognitive effect of underwater operations and the underlying mechanism remain elusive. Here, we found a single underwater operation affects cognition in a time-dependent model. Prolonged exposure elicits significant cognitive impairment and hippocampal dysfunction, which was accompanied by activation of microglia and upregulation of pro-inflammatory cytokines. RNA-sequencing supported the involvement of neuroinflammation and indicated the critical role of CCR3. Knockdown of CCR3 significantly rescued cognitive impairment and hippocampal dysfunction. Furthermore, the upregulation of pro-inflammatory cytokines was also reversed. Mechanistically, CCR3 knockdown switched the activated microglia from a pro-inflammatory to neuroprotective phenotype. Taken together, these results highlighted the time-dependent effects of a single underwater operation on cognitive function. Knocking down CCR3 can attenuate neuroinflammation by regulating polarization of activated microglia, thereby alleviating prolonged underwater operation-induced cognitive impairment.
Project description:Despite smell impairment has been considered a potential non-motor finding in ALS, the pathobiochemistry at olfactory level remains unknown. Here, we applied an olfactory quantitative proteotyping approach to analyze the magnitude of the olfactory bulb (OB) proteostatic imbalance in ALS subjects (n=12) respect to controls (n=8).
Project description:Olfactory dysfunction is one of the earliest features in Lewy-type alpha-synucleinopathies (LTS) such as Parkinson´s disease (PD). However, the underlying molecular mechanisms associated to smell impairment is poorly understood. To reveal the missing links in the biochemical understanding of olfactory dysfunction in PD, we have applied mass spectrometry-based proteomics in postmortem olfactory bulbs (OBs) dissected from parkinsonian subjects with different LTS staging respect to elderly controls (n= 24, mean age 79 years).
Project description:In this study, we carried out a large-scale proteome profiling of human mitral valve tissues resected from patients with mitral valve prolapse.
Project description:Mitral and tricuspid valves are essential for unidirectional blood flow in the heart. They are derived from similar cell sources, and yet congenital dysplasia affecting both valves is clinically rare, suggesting the presence of differential regulatory mechanisms underlying their development. We specifically inactivated Dicer1 in the endocardium during cardiogenesis and found that Dicer1-deletion caused congenital mitral valve stenosis and regurgitation, while it had no impact on other valves. We showed that hyperplastic mitral valves were caused by abnormal condensation and extracellular matrix (ECM) remodeling. Our single-cell RNA Sequencing analysis revealed impaired maturation of mesenchymal cells and abnormal expression of ECM genes in mutant mitral valves. Furthermore, expression of a set of miRNAs that target ECM genes was significantly lower in tricuspid valves compared to mitral valves, consistent with the idea that the miRNAs are differentially required for mitral and tricuspid valve development. We thus reveal miRNA-mediated gene regulation as a novel molecular mechanism that differentially regulates mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.
Project description:Evaluation of global expression patterns provides a molecular portrait of mitral valve disease, yields insight into the pathophysiologic aspects of DMVD, and identifies intriguing genes and pathways for further study. (Am J Vet Res 2006;67:1307–1318) Keywords: control vs diseased 4 controls( beagle crosses) and 4 affected (1 Daschund, 1 Lhasa apso, 2 miniature poodles)