scholarly journals A comprehensive p75 neurotrophin receptor gene network and pathway analyses identifying new target genes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Antti Sajanti ◽  
Seán B. Lyne ◽  
Romuald Girard ◽  
Janek Frantzén ◽  
Tomi Rantamäki ◽  
...  
Keyword(s):  
Gene Network ◽  
Brain Plasticity ◽  
Initial Point ◽  
Cellular Damage ◽  
Neurotrophin Receptor ◽  
Signaling Networks ◽  
Network Analyses ◽  
Pathway Analyses ◽  
General Response

Abstract P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred, which makes p75NTR’s related signaling networks an interesting and challenging initial point of investigation. We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years. Bioinformatic network and pathway analyses of identified genes (n = 235) were performed using ReactomeFIViz in Cytoscape based on the highly reliable Reactome functional interaction network algorithm. This approach merges interactions extracted from human curated pathways with predicted interactions from machine learning. Genome-wide pathway analysis showed total of 16 enriched hierarchical clusters. A total of 278 enriched single pathways were also identified (p < 0.05, false discovery rate corrected). Gene network analyses showed multiple known and new targets in the p75NTR gene network. This study provides a comprehensive analysis and investigation into the current knowledge of p75NTR signaling networks and pathways. These results also identify several genes and their respective protein products as involved in the p75NTR network, which have not previously been clearly studied in this pathway. These results can be used to generate novel hypotheses to gain a greater understanding of p75NTR in acute brain injuries, neurodegenerative diseases and general response to cellular damage.

Abstract P809: A Comprehensive P75 Neurotrophin Receptor Gene Network and Pathway Analyses Identifying New Target Genes for Stroke Recovery

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Antti Sajanti ◽  
Séan Lyne ◽  
Romuald Girard ◽  
Janek Frantzen ◽  
Tomi Rantamaki ◽  
...  
Keyword(s):  
Gene Network ◽  
Target Genes ◽  
Brain Plasticity ◽  
Current Knowledge ◽  
Receptor Gene ◽  
Stroke Recovery ◽  
Neurotrophin Receptor ◽  
Network Analyses ◽  
Pathway Analyses

Introduction: Therapeutic interest into the neurotrophins resides in their ability to regulate the process of neuronal and synaptic regeneration following acute brain injuries such as intracerebral hemorrhage, subarachnoid hemorrhage and ischemic stroke. P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred. Methods: We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years. Bioinformatic network and pathway analyses of identified genes (n=235) were performed using ReactomeFIViz in Cytoscape based on the highly reliable Reactome functional interaction network algorithm. This approach merges interactions extracted from human curated pathways with predicted interactions from machine learning. Results: Genome-wide pathway analysis showed total of 16 enriched hierarchical clusters. A total of 278 enriched single pathways were also identified (p<0.05, FDR corrected). Gene network analyses showed multiple known and new targets in the p75NTR gene network. This study provides a comprehensive analysis and investigation into the current knowledge of p75NTR signaling networks and pathways. Discussion: This study provides the largest comprehensive gene and functional network library of p75NTR and incorporates current knowledge using a large dataset approach that increases the overall understanding of complex p75NTR networks. These results suggest both new possible target genes for further investigation in p75NTR research, while also validating previously conducted research. These results can be used to generate novel hypotheses to gain a greater understanding of p75NTR in stroke. Future directions: We are currently sequencing miRNA libraries from ischemic and hemorrhagic stroke patients’ plasma with longitudinal plasma samples and clinical data. This data together with presented results will be used to test identified novel targets in p75NTR engineered models in order seek novel therapeutic strategies to increase recovery after stroke.

scholarly journals Genes with high network connectivity are enriched for disease heritability

2018 ◽  
Author(s):  
Samuel S. Kim ◽  
Chengzhen Dai ◽  
Farhad Hormozdiari ◽  
Bryce van de Geijn ◽  
Steven Gazal ◽  
...  
Keyword(s):  
Complex Traits ◽  
Gene Networks ◽  
Gene Network ◽  
Network Connectivity ◽  
Biological Mechanisms ◽  
Pathway Network ◽  
Network Analyses ◽  
Disease Biology ◽  
Significant Pathway

AbstractRecent studies have highlighted the role of gene networks in disease biology. To formally assess this, we constructed a broad set of pathway, network, and pathway+network annotations and applied stratified LD score regression to 42 independent diseases and complex traits (average N=323K) to identify enriched annotations. First, we constructed annotations from 18,119 biological pathways, including 100kb windows around each gene. We identified 156 pathway-trait pairs whose disease enrichment was statistically significant (FDR < 5%) after conditioning on all genes and on annotations from the baseline-LD model, a stringent step that greatly reduced the number of pathways detected; most of the significant pathway-trait pairs were previously unreported. Next, for each of four published gene networks, we constructed probabilistic annotations based on network connectivity using closeness centrality, a measure of how close a gene is to other genes in the network. For each gene network, the network connectivity annotation was strongly significantly enriched. Surprisingly, the enrichments were fully explained by excess overlap between network annotations and regulatory annotations from the baseline-LD model, validating the informativeness of the baseline-LD model and emphasizing the importance of accounting for regulatory annotations in gene network analyses. Finally, for each of the 156 enriched pathway-trait pairs, for each of the four gene networks, we constructed pathway+network annotations by annotating genes with high network connectivity to the input pathway. For each gene network, these pathway+network annotations were strongly significantly enriched for the corresponding traits. Once again, the enrichments were largely explained by the baseline-LD model. In conclusion, gene network connectivity is highly informative for disease architectures, but the information in gene networks may be subsumed by regulatory annotations, such that accounting for known annotations is critical to robust inference of biological mechanisms.

scholarly journals Functional and gene network analyses of transcriptional signatures characterizing pre-weaned bovine mammary parenchyma or fat pad uncovered novel inter-tissue signaling networks during development

BMC Genomics ◽  
2010 ◽  
Vol 11 (1) ◽  
pp. 331 ◽  
Author(s):  
Paola Piantoni ◽  
Massimo Bionaz ◽  
Daniel E Graugnard ◽  
Kristy M Daniels ◽  
Robin E Everts ◽  
...  
Keyword(s):  
Gene Network ◽  
Signaling Networks ◽  
Fat Pad ◽  
Network Analyses

scholarly journals Molecular pathology associated with altered synaptic transcriptome in the dorsolateral prefrontal cortex of depressed subjects

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuta Yoshino ◽  
Bhaskar Roy ◽  
Nilesh Kumar ◽  
M. Shahid Mukhtar ◽  
Yogesh Dwivedi
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Prefrontal Cortex ◽  
Dorsolateral Prefrontal Cortex ◽  
Gene Network ◽  
Nervous System Development ◽  
Network Analyses ◽  
Dorsolateral Prefrontal ◽  
Total Fraction ◽  
Transcriptomic Changes

AbstractDisrupted synaptic plasticity is the hallmark of major depressive disorder (MDD), with accompanying changes at the molecular and cellular levels. Often, the maladaptive molecular changes at the synapse are the result of global transcriptional reprogramming dictated by activity-dependent synaptic modulation. Thus far, no study has directly studied the transcriptome-wide expression changes locally at the synapse in MDD brain. Here, we have examined altered synaptic transcriptomics and their functional relevance in MDD with a focus on the dorsolateral prefrontal cortex (dlPFC). RNA was isolated from total fraction and purified synaptosomes of dlPFC from well-matched 15 non-psychiatric controls and 15 MDD subjects. Transcriptomic changes in synaptic and total fractions were detected by next-generation RNA-sequencing (NGS) and analyzed independently. The ratio of synaptic/total fraction was estimated to evaluate a shift in gene expression ratio in MDD subjects. Bioinformatics and network analyses were used to determine the biological relevance of transcriptomic changes in both total and synaptic fractions based on gene–gene network, gene ontology (GO), and pathway prediction algorithms. A total of 14,005 genes were detected in total fraction. A total of 104 genes were differentially regulated (73 upregulated and 31 downregulated) in MDD group based on 1.3-fold change threshold and p < 0.05 criteria. In synaptosomes, out of 13,236 detectable genes, 234 were upregulated and 60 were downregulated (>1.3-fold, p < 0.05). Several of these altered genes were validated independently by a quantitative polymerase chain reaction (qPCR). GO revealed an association with immune system processes and cell death. Moreover, a cluster of genes belonged to the nervous system development, and psychological disorders were discovered using gene–gene network analysis. The ratio of synaptic/total fraction showed a shift in expression of 119 genes in MDD subjects, which were primarily associated with neuroinflammation, interleukin signaling, and cell death. Our results suggest not only large-scale gene expression changes in synaptosomes, but also a shift in the expression of genes from total to synaptic fractions of dlPFC of MDD subjects with their potential role in immunomodulation and cell death. Our findings provide new insights into the understanding of transcriptomic regulation at the synapse and their possible role in MDD pathogenesis.

scholarly journals 20-HETE-mediated cytotoxicity and apoptosis in ischemic kidney epithelial cells

2008 ◽  
Vol 294 (3) ◽  
pp. F562-F570 ◽  
Author(s):  
Vani Nilakantan ◽  
Cheryl Maenpaa ◽  
Guangfu Jia ◽  
Richard J. Roman ◽  
Frank Park
Keyword(s):  
Caspase 3 ◽  
Fluorescent Protein ◽  
Ischemia Reperfusion ◽  
Atp Depletion ◽  
Cellular Damage ◽  
Apoptotic Pathway ◽  
Injury Model ◽  
Green Fluorescent

20-HETE, a metabolite of arachidonic acid, has been implicated as a mediator of free radical formation and tissue death following ischemia-reperfusion (IR) injury in the brain and heart. The present study examined the role of this pathway in a simulated IR renal injury model in vitro. Modified self-inactivating lentiviral vectors were generated to stably overexpress murine Cyp4a12 following transduction into LLC-PK1 cells (LLC-Cyp4a12). We compared the survival of control and transduced LLC-PK1 cells following 4 h of ATP depletion and 2 h of recovery in serum-free medium. ATP depletion-recovery of LLC-Cyp4a12 cells resulted in a significantly higher LDH release ( P < 0.05) compared with LLC-enhanced green fluorescent protein (EGFP) cells. Treatment with the SOD mimetic MnTMPyP (100 μM) resulted in decreased cytotoxicity in LLC-Cyp4a12 cells. The selective 20-HETE inhibitor HET-0016 (10 μM) also inhibited cytotoxicity significantly ( P < 0.05) in LLC-Cyp4a12 cells. Dihydroethidium fluorescence showed that superoxide levels were increased to the same degree in LLC-EGFP and LLC-Cyp4a12 cells after ATP depletion-recovery compared with control cells and that this increase was inhibited by MnTMPyP. There was a significant increase ( P < 0.05) of caspase-3 cleavage, an effector protease of the apoptotic pathway, in the LLC-Cyp4a12 vs. LLC-EGFP cells ( P < 0.05). This was abolished in the presence of HET-0016 ( P < 0.05) or MnTMPyP ( P < 0.01). These results demonstrate that 20-HETE overexpression can significantly exacerbate the cellular damage that is associated with renal IR injury and that the programmed cell death is mediated by activation of caspase-3 and is partially dependent on enhanced CYP4A generation of free radicals.

scholarly journals Role of phospholipase Cε in physiological phosphoinositide signaling networks

2012 ◽  
Vol 24 (6) ◽  
pp. 1333-1343 ◽  
Author(s):  
Alan V. Smrcka ◽  
Joan Heller Brown ◽  
George G. Holz
Keyword(s):  
Signaling Networks ◽  
Phosphoinositide Signaling ◽  
Phospholipase Cε

scholarly journals Aging-associated changes in microRNA expression profile of internal anal sphincter smooth muscle: Role of microRNA-133a

2016 ◽  
Vol 311 (5) ◽  
pp. G964-G973 ◽  
Author(s):  
Jagmohan Singh ◽  
Ettickan Boopathi ◽  
Sankar Addya ◽  
Benjamin Phillips ◽  
Isidore Rigoutsos ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Anal Sphincter ◽  
Internal Anal Sphincter ◽  
Smooth Muscles ◽  
Smooth Muscle Contractility ◽  
Network Analyses ◽  
Rhoa Signaling

A comprehensive genomic and proteomic, computational, and physiological approach was employed to examine the (previously unexplored) role of microRNAs (miRNAs) as regulators of internal anal sphincter (IAS) smooth muscle contractile phenotype and basal tone. miRNA profiling, genome-wide expression, validation, and network analyses were employed to assess changes in mRNA and miRNA expression in IAS smooth muscles from young vs. aging rats. Multiple miRNAs, including rno-miR-1, rno-miR-340-5p, rno-miR-185, rno-miR-199a-3p, rno-miR-200c, rno-miR-200b, rno-miR-31, rno-miR-133a, and rno-miR-206, were found to be upregulated in aging IAS. qPCR confirmed the upregulated expression of these miRNAs and downregulation of multiple, predicted targets ( Eln, Col3a1, Col1a1, Zeb2, Myocd, Srf, Smad1, Smad2, Rhoa/Rock2, Fn1, Tagln v2, Klf4, and Acta2) involved in regulation of smooth muscle contractility. Subsequent studies demonstrated an aging-associated increase in the expression of miR-133a, corresponding decreases in RhoA, ROCK2, MYOCD, SRF, and SM22α protein expression, RhoA-signaling, and a decrease in basal and agonist [U-46619 (thromboxane A2analog)]-induced increase in the IAS tone. Moreover, in vitro transfection of miR-133a caused a dose-dependent increase of IAS tone in strips, which was reversed by anti-miR-133a. Last, in vivo perianal injection of anti-miR-133a reversed the loss of IAS tone associated with age. This work establishes the important regulatory effect of miRNA-133a on basal and agonist-stimulated IAS tone. Moreover, reversal of age-associated loss of tone via anti-miR delivery strongly implicates miR dysregulation as a causal factor in the aging-associated decrease in IAS tone and suggests that miR-133a is a feasible therapeutic target in aging-associated rectoanal incontinence.

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