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Plasma Biomarkers for VX exposure in guinea pigs

ABSTRACT: Biomarker discovery using plasma obtained from exposed guinea pigs (N=6) exposed to VX.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Cavia Porcellus (guinea Pig)

TISSUE(S): Blood Plasma

SUBMITTER: Trevor Glaros

LAB HEAD: Trevor Glaros

PROVIDER: PXD017254 | Pride | 2020-08-03

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	GP39_Plasma_.msf	Msf
	GP39_Plasma_END.raw	Raw
	GP39_Plasma_F1.raw	Raw
	GP39_Plasma_F10.raw	Raw
	GP39_Plasma_F11.raw	Raw

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Publications

Discovery of treatment for nerve agents targeting a new metabolic pathway.

Glaros Trevor T Dhummakupt Elizabeth S ES Rizzo Gabrielle M GM McBride Ethan E Carmany Daniel O DO Wright Linnzi K M LKM Forster Jeffry S JS Renner Julie A JA Moretz Ruth W RW Dorsey Russell R Marten Mark R MR Huso Walker W Doan Alexander A Dorsey Carrie D CD Phillips Christopher C Benton Bernard B Mach Phillip M PM

Archives of toxicology 20200727 9

The inhibition of acetylcholinesterase is regarded as the primary toxic mechanism of action for chemical warfare agents. Recently, there have been numerous reports suggesting that metabolic processes could significantly contribute to toxicity. As such, we applied a multi-omics pipeline to generate a detailed cascade of molecular events temporally occurring in guinea pigs exposed to VX. Proteomic and metabolomic profiling resulted in the identification of several enzymes and metabolic precursors ...[more]

PMID: 32720192

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Phosphoproteomic Analysis Suggests Compensatory Effects in the Piriform Cortex Region of the VX-Exposed Rat

Project description:To gain insight into the toxicity induced by VX, a mass spectrometry based phosphoproteomics approach was employed to understand the signaling modulated by VX toxicity in piriform cortex region of the rat brain. We have employed isobaric-based TMT labeling and titanium dioxide- based enrichment strategy to identify and quantify the changes that are modulated by VX. We observed a temporal association of changes in the phosphorylation status of proteins over a 24 hour time course in rats exposed to 1x LD50 VX, with the most notable changes by the first measured time point, 1 hour post exposure. These data fell into five main functional classes of proteins directly or indirectly influenced by changes in phosphorylation: 1) Ion channels/transporters, including ATPases, 2) Kinases/Phosphatases, 3) GTPases, 4) Structural related proteins, and 5) Transcriptional regulatory proteins. This study is the first quantitative phosphoproteomics analysis of VX toxicity in the brain. Understanding the toxicity and compensatory signaling mechanisms will improve the understanding of the complex toxicity of VX in the brain, and aid in the elucidation of novel molecular targets allowing for improved countermeasure development.

2015-01-07 | PXD001184 | Pride

Gene expression changes in human cardiomyocytes exposed to VX (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothiolate)

Project description:Organophosphorus compounds induce cardiotoxicity through currently unknown mechanisms, which need to be unraveled by a comprehensive and systematic approach such as genome-wide gene expression analysis. We used microarrays to study gene expression changes in human cardiomyocytes after exposure to VX, and identified pathways underlying these changes. Human cardiomyocytes were exposed to sublethal concentrations (0, 0.1, 10 μM) of VX. RNA were extracted at different timepoints (0, 6, 24, 72 h) after VX exposure and hybridized to Affymetrix microarrays. Four biological repeats were used for each condition.

2011-10-28 | E-GEOD-33325 | biostudies-arrayexpress

Gene expression changes in human hepatocytes exposed to VX (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothiolate)

Project description:Organophosphorus compounds induce hepatotoxicity through currently unknown mechanisms, which need to be unraveled by a comprehensive and systematic approach such as genome-wide gene expression analysis. We used microarrays to study gene expression changes in human hepatocytes after exposure to VX, and identified pathways underlying these changes. Human hepatocytes were exposed to sublethal concentrations (0, 0.1, 10 μM) of VX. RNA were extracted at different timepoints (0, 6 h) after VX exposure and hybridized to Affymetrix microarrays. Four biological repeats were used for each condition.

2011-11-11 | E-GEOD-33606 | biostudies-arrayexpress

Gene expression changes in human neural cells exposed to VX (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothiolate)

Project description:Organophosphorus compounds may induce neurotoxicity through mechanisms other than the cholinergic pathway, which need to be unraveled by a comprehensive and systematic approach such as genome-wide gene expression analysis. We used microarrays to study gene expression changes in human neural cells after exposure to VX, and identified pathways underlying these changes. Human neural cells were exposed to sublethal concentrations (0, 0.1, 10 μM) of VX. RNA were extracted at different timepoints (0, 6, 24, 72 h) after VX exposure and hybridized to Affymetrix microarrays. Four biological repeats were used for each condition.

2011-10-20 | E-GEOD-33109 | biostudies-arrayexpress

Genome-wide analysis of gene expression in influenza A infected human macrophages treated with VX-787

2016-04-03 | GSE79854 | GEO

Genome-wide analysis of gene expression in influenza A infected human macrophages treated with VX-787

Project description:Analysis of gene expression in macrophages infected with influenza A virus or Mock and treated with the VX-787 to investigate the effects VX-787 have on transcriptional response in human macrophages. Human macrophages were infected with influenza A/WSN/1933(H1N1) or A/Udorn/307/72(H3N2) viruses, or non-infected (Mock). 10nM VX-787 was treated to WSN, Udorn or Mock infected cells, repectively.

2016-04-03 | E-GEOD-79854 | biostudies-arrayexpress

Gene expression changes in human cardiomyocytes exposed to VX (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothiolate)

2011-10-29 | GSE33325 | GEO

Gene expression changes in human hepatocytes exposed to VX (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothiolate)

2011-11-11 | GSE33606 | GEO

Elexacaftor/VX-445-mediated CFTR interactome remodeling reveals differential correction driven by mutation-specific translational dynamics

Project description:Cystic fibrosis (CF) is one of the most prevalent lethal genetic diseases with over 2000 identified genetic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pharmacological chaperones such as Lumacaftor (VX-809), Tezacaftor (VX-661) and Elexacaftor (VX-445) treat mutation-induced defects by stabilizing CFTR and are called correctors. These correctors improve proper folding and thus facilitate processing and trafficking to increase the amount of functional CFTR on the cell surface. Yet, CFTR variants display differential responses to each corrector. Here, we report variants P67L and L206W respond similarly to VX-809 but divergently to VX-445 with P67L exhibiting little rescue when treated with VX-445. We investigate the underlying cellular mechanisms of how CFTR biogenesis is altered by correctors in these variants. Affinity purification-mass spectrometry (AP-MS) multiplexed with isobaric Tandem Mass Tags (TMT) was used to quantify CFTR protein-protein interaction changes between variants P67L and L206W. VX-445 facilitates unique proteostasis factor interactions especially in translation, folding, and degradation pathways in a CFTR variant-dependent manner. A number of these interacting proteins knocked down by siRNA, such as ribosomal subunit proteins, moderately rescued fully glycosylated P67L. Importantly, these knock-downs sensitize P67L to VX-445 and further enhance the correction of this variant. Our results provide a better understanding of VX-445 biological mechanism of action and reveal cellular targets that may sensitize unresponsive CFTR variants to known and available correctors.

2023-09-18 | PXD039773 | Pride

microRNA (miRNA) expression data from induced pluripotent stem cell (iPSC)-derived neurons exposed to VX

Project description:Chemical warfare nerve agents (CWNA) are potent cholinesterase inhibitors that may also have non-cholinesterase effects. Several in vivo studies have shown that exposure to CWNA compounds induces damage in the brain and heart. Underlying mechanisms of this damage are a critical area of research for the development of medical countermeasures. This study utilized microRNA (miRNA) analysis to evaluate potential direct cellular effects of the nerve agent VX (o-ethyl-s-[2 (diisopropylamino) ethyl] methylphosphonothiolate) on human-induced pluripotent stem cell (iPSC)-derived neurons iPSC-derived neurons were treated with VX at concentrations of 0µM (saline control), 0.1µM or 100µM for either 1 hour or 6 hours. Total RNA was then isolated and processed for miRNA microarray analysis using Affymetrix miRNA 2.0 GeneChips

2013-12-31 | E-GEOD-48670 | biostudies-arrayexpress

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