Summary of Study ST002243

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001432. The data can be accessed directly via it's Project DOI: 10.21228/M8MQ5M This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002243
Study TitleLipidomics analysis of Friedreich's ataxia (FRDA) (part II)
Study TypeUntargeted and targeted (PRM) analysis
Study SummaryFriedreich’s Ataxia (FRDA) is an autosomal neurodegenerative disease caused by the deficiency of protein frataxin. Frataxin functions in the assembly of iron-sulfur clusters that are important for iron homeostasis and metabolic functions. To identify metabolic features that can be used for potential biomarkers in FRDA plasma, we performed a targeted multi-omics (metabolomics, lipidomics, and proteomics) analysis using discovery-validation cohort design. Muti-omics analysis revealed that FRDA patients had dysregulated sphingolipid metabolism, phospholipid metabolism, citric acid cycle, amino acid metabolism, and apolipoprotein metabolism. Sphingolipid dysfunctions were revealed by decreased very long chain ceramides but unchanged long chain ceramides in FRDA plasma, which resulted in the increased ratio of long chain ceramides to very long chain ceramides. Decreased very long chain ceramides distinguished FRDA patients from healthy controls and showed good predictive capacities with AUC values from 0.75 to 0.85. Furthermore, by performing lipidomic and stable isotope tracing experiment in induced pluripotent stem cell differentiated cardiomyocytes (iPSC-CMs, we demonstrated that frataxin deficiency affected ceramide synthase (CerS2), and preferentially enriched long chain ceramides and depleted very long chain ceramides. Moreover, ceramide metabolism was differentially regulated in a tissue-specific manner. Finally, machine learning model increased the prediction of FRDA using the combination of three metabolites (AUC > 0.9). In conclusion, decreased very long chain ceramides are potential biomarkers and therapeutic target in FRDA patients.
Institute
University of Pennsylvania
Last NameWang
First NameDezhen
Address421 Curie Blvd, Philadelphia, PA, 19104, USA
Emaildezhen.wang@pennmedicine.upenn.edu
Phone5312185610
Submit Date2022-07-29
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2022-08-22
Release Version1
Dezhen Wang Dezhen Wang
https://dx.doi.org/10.21228/M8MQ5M
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR001432
Project DOI:doi: 10.21228/M8MQ5M
Project Title:Multi-omics study of Friedreich's ataxia (FRDA)
Project Type:Untargeted and targeted (PRM) analysis
Project Summary:Multi-omics study of plasma samples from FRDA patients and healthy controls
Institute:University of Pennsylvania
Last Name:Wang
First Name:Dezhen
Address:421 Curie Blvd, Philadelphia, PA, 19104, USA
Email:dezhen.wang@pennmedicine.upenn.edu
Phone:5312185610

Subject:

Subject ID:SU002329
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Group
SA214164Negative_QC_5-
SA214165Negative_QC_4-
SA214166Negative_QC_6-
SA214167Negative_QC_8-
SA214168Negative_QC_9-
SA214169Negative_QC_3-
SA214170Negative_QC_7-
SA214171Negative_QC_2-
SA214172Negative_QC_11-
SA214173Negative_QC_10-
SA214174Negative_QC_12-
SA214175Negative_QC_14-
SA214176Negative_QC_16-
SA214177Negative_QC_15-
SA214178Positive_QC_9-
SA214179Positive_QC_8-
SA214180Positive_QC_13-
SA214181Positive_QC_14-
SA214182Positive_QC_12-
SA214183Positive_QC_11-
SA214184Positive_QC_1-
SA214185Positive_QC_10-
SA214186Positive_QC_15-
SA214187Positive_QC_16-
SA214188Positive_QC_6-
SA214189Positive_QC_7-
SA214190Positive_QC_5-
SA214191Positive_QC_4-
SA214192Positive_QC_2-
SA214193Positive_QC_3-
SA214194Negative_QC_1-
SA214195Negative_QC_13-
SA214196Carrier_Positive_P-20Carrier
SA214197Carrier_Positive_P-19Carrier
SA214198Carrier_Positive_P-17Carrier
SA214199Carrier_Positive_P-16Carrier
SA214200Carrier_Positive_P-21Carrier
SA214201Carrier_Positive_P-22Carrier
SA214202Carrier_Positive_P-25Carrier
SA214203Carrier_Positive_P-24Carrier
SA214204Carrier_Positive_P-23Carrier
SA214205Carrier_Negative_P-26Carrier
SA214206Carrier_Negative_P-25Carrier
SA214207Carrier_Negative_P-19Carrier
SA214208Carrier_Negative_P-18Carrier
SA214209Carrier_Negative_P-17Carrier
SA214210Carrier_Negative_P-16Carrier
SA214211Carrier_Negative_P-20Carrier
SA214212Carrier_Negative_P-21Carrier
SA214213Carrier_Negative_P-24Carrier
SA214214Carrier_Negative_P-23Carrier
SA214215Carrier_Negative_P-22Carrier
SA214216Carrier_Positive_P-26Carrier
SA214217Carrier_Positive_P-18Carrier
SA214218Control_Positive_OP_15Control
SA214219Control_Positive_OP_16Control
SA214220Control_Positive_OP_14Control
SA214221Control_Negative_P-14Control
SA214222Control_Negative_OP_9Control
SA214223Control_Positive_OP_17Control
SA214224Control_Positive_OP_18Control
SA214225Control_Negative_OP_15Control
SA214226Control_Negative_OP_16Control
SA214227Control_Negative_OP_14Control
SA214228Control_Positive_OP_35Control
SA214229Control_Positive_OP_19Control
SA214230Control_Negative_P-13Control
SA214231Control_Negative_P-12Control
SA214232Control_Negative_P-04Control
SA214233Control_Negative_P-05Control
SA214234Control_Positive_OP_40Control
SA214235Control_Negative_P-02Control
SA214236Control_Negative_P-01Control
SA214237Control_Negative_P-06Control
SA214238Control_Negative_P-07Control
SA214239Control_Negative_P-11Control
SA214240Control_Negative_P-10Control
SA214241Control_Negative_P-09Control
SA214242Control_Negative_P-08Control
SA214243Control_Negative_OP_17Control
SA214244Control_Negative_P-03Control
SA214245Control_Positive_P-05Control
SA214246Control_Positive_P-04Control
SA214247Control_Positive_P-06Control
SA214248Control_Positive_P-07Control
SA214249Control_Positive_P-08Control
SA214250Control_Positive_P-03Control
SA214251Control_Positive_P-02Control
SA214252Control_Positive_OP_41Control
SA214253Control_Negative_OP_18Control
SA214254Control_Positive_OP_8Control
SA214255Control_Positive_OP_9Control
SA214256Control_Positive_P-01Control
SA214257Control_Positive_P-09Control
SA214258Control_Positive_OP_42Control
SA214259Control_Negative_OP_35Control
SA214260Control_Negative_OP_40Control
SA214261Control_Negative_OP_19Control
SA214262Control_Positive_P-10Control
SA214263Control_Negative_OP_42Control
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Collection:

Collection ID:CO002322
Collection Summary:Venous blood was drawn in 8.5 mL purple cap Vacutainer EDTA tubes and gently invert to mix. Plasma was collected after centrifugation at 1000 g for 15 min. All samples were immediately aliquoted to Eppendorf tubes and frozen at -80 ºC until analysis.
Sample Type:Blood (plasma)
Storage Conditions:-80℃

Treatment:

Treatment ID:TR002341
Treatment Summary:NA

Sample Preparation:

Sampleprep ID:SP002335
Sampleprep Summary:50 μL plasma, was mixed with 20 μL internal standard working solution (SPLASH® LIPIDOMIX® Mass Spec Standard + Cer/sph mixture I), extracted with 1000 μL butanol/methanol (1/1, v/v, 10 mM ammonium formate) for 10 min on a vortex mixture. Samples were pelleted by centrifugation at 4000 x g for 5 min at room temperature. The supernatant was moved to a clean glass tube, dried under nitrogen, and resuspended in 100 μL MTBE/methanol (1/3, v/v) with 10 mM ammonium formate. 5 μL of each sample was combined to make a pooled quality control (QC) sample and ran every ten samples in the long sequence to monitor retention time and signal intensity drift. The remaining samples (50 μL) were transferred into injection vials for lipidomic analysis.

Combined analysis:

Analysis ID AN003661 AN003662
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Thermo Dionex Ultimate 3000 Thermo Dionex Ultimate 3000
Column Thermo Accucore C18 (100 x 2.1mm,2.6um) Thermo Accucore C18 (100 x 2.1mm,2.6um)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive HF hybrid Orbitrap Thermo Q Exactive HF hybrid Orbitrap
Ion Mode POSITIVE NEGATIVE
Units intensity intensity

Chromatography:

Chromatography ID:CH002713
Instrument Name:Thermo Dionex Ultimate 3000
Column Name:Thermo Accucore C18 (100 x 2.1mm,2.6um)
Column Temperature:35
Flow Gradient:0 min, 90% A; 1 min, 90% A; 4 min, 60% A; 12 min, 25% A; 21 min, 1% A; 24 min, 1% A; 24.1 min, 90% A; 28 min, 90%.
Flow Rate:0.4 ml/min
Injection Temperature:4
Solvent A:50% acetonitrile/50% water; 0.1% formic acid; 10 mM ammonium formate
Solvent B:10% acetonitrile/88% isopropanol/2% water; 0.02% formic acid; 2 mM ammonium formate
Analytical Time:28min
Chromatography Type:Reversed phase

MS:

MS ID:MS003412
Analysis ID:AN003661
Instrument Name:Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Samples were analyzed using a Q Exactive HF (QE-HF) (Thermo Scientific, Waltham, MA) equipped with a heated electro-spray ionization (HESI) source operated in both positive and negative ion mode. For DDA library generation (untargeted lipidomics), data acquisition was performed on the pooled QC samples in Full Scan/ddMS2 mode @ 120,000 resolutions. The Full Scan settings as follows: AGC target = 1e6; Maximum IT = 250 ms; scan range = 250 to 1800 m/z. Top 20 MS/MS spectral (dd-MS2) @ 15000 were generated with AGC target = 1e5, Maximum IT=25 ms, and (N)CE/stepped nce = 20, 30, 40v. For untargeted lipid analysis, LipidSearch 4.2 (Thermo Scientific, Waltham, MA) was used for peak detection, identification, alignment, and quantification. Well annotated lipids (MS spectral match) were used to generate a inclusion list (Supplementary Table 4) for targeted lipidomics analysis. Targeted lipidomics were performed in Full scan + PRM modes. The PRM settings were as follows: resolution = 15000, AGC target = 2e5, Maximum IT=25 ms, loop count = 36, isolation window = 2.0, (N)CE was optimized for each lipid class.
Ion Mode:POSITIVE
  
MS ID:MS003413
Analysis ID:AN003662
Instrument Name:Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Samples were analyzed using a Q Exactive HF (QE-HF) (Thermo Scientific, Waltham, MA) equipped with a heated electro-spray ionization (HESI) source operated in both positive and negative ion mode. For DDA library generation (untargeted lipidomics), data acquisition was performed on the pooled QC samples in Full Scan/ddMS2 mode @ 120,000 resolutions. The Full Scan settings as follows: AGC target = 1e6; Maximum IT = 250 ms; scan range = 250 to 1800 m/z. Top 20 MS/MS spectral (dd-MS2) @ 15000 were generated with AGC target = 1e5, Maximum IT=25 ms, and (N)CE/stepped nce = 20, 30, 40v. For untargeted lipid analysis, LipidSearch 4.2 (Thermo Scientific, Waltham, MA) was used for peak detection, identification, alignment, and quantification. Well annotated lipids (MS spectral match) were used to generate a inclusion list (Supplementary Table 4) for targeted lipidomics analysis. Targeted lipidomics were performed in Full scan + PRM modes. The PRM settings were as follows: resolution = 15000, AGC target = 2e5, Maximum IT=25 ms, loop count = 36, isolation window = 2.0, (N)CE was optimized for each lipid class.
Ion Mode:NEGATIVE
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