Summary of Study ST002244

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.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

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 IDST002244
Study TitleMetabolomics analysis of Friedreich's ataxia (FRDA) (part I)
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:SU002330
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
SA214388Negative_QC_13-
SA214389Negative_QC_14-
SA214390Negative_QC_15-
SA214391Negative_QC_1-
SA214392Negative_QC_12-
SA214393Negative_QC_10-
SA214394Negative_QC_11-
SA214395Negative_QC_16-
SA214396Negative_QC_2-
SA214397Negative_QC_7-
SA214398Negative_QC_6-
SA214399Negative_QC_8-
SA214400Negative_QC_9-
SA214401Negative_QC_3-
SA214402Negative_QC_4-
SA214403Positive_QC_1-
SA214404Positive_QC_10-
SA214405Positive_QC_5-
SA214406Positive_QC_4-
SA214407Positive_QC_6-
SA214408Positive_QC_7-
SA214409Positive_QC_9-
SA214410Positive_QC_8-
SA214411Positive_QC_3-
SA214412Positive_QC_2-
SA214413Positive_QC_12-
SA214414Positive_QC_11-
SA214415Positive_QC_13-
SA214416Positive_QC_14-
SA214417Positive_QC_16-
SA214418Positive_QC_15-
SA214419Negative_QC_5-
SA214420Carrier_Positive_P-23Carrier
SA214421Carrier_Positive_P-22Carrier
SA214422Carrier_Positive_P-24Carrier
SA214423Carrier_Positive_P-25Carrier
SA214424Carrier_Positive_P-26Carrier
SA214425Carrier_Positive_P-21Carrier
SA214426Carrier_Positive_P-20Carrier
SA214427Carrier_Positive_P-17Carrier
SA214428Carrier_Positive_P-18Carrier
SA214429Carrier_Positive_P-19Carrier
SA214430Carrier_Negative_P-16Carrier
SA214431Carrier_Positive_P-16Carrier
SA214432Carrier_Negative_P-22Carrier
SA214433Carrier_Negative_P-23Carrier
SA214434Carrier_Negative_P-24Carrier
SA214435Carrier_Negative_P-25Carrier
SA214436Carrier_Negative_P-21Carrier
SA214437Carrier_Negative_P-26Carrier
SA214438Carrier_Negative_P-17Carrier
SA214439Carrier_Negative_P-20Carrier
SA214440Carrier_Negative_P-18Carrier
SA214441Carrier_Negative_P-19Carrier
SA214442Control_Negative_OP_40Control
SA214443Control_Positive_OP_14Control
SA214444Control_Negative_OP_8Control
SA214445Control_Positive_OP_15Control
SA214446Control_Negative_OP_42Control
SA214447Control_Negative_OP_41Control
SA214448Control_Positive_OP_18Control
SA214449Control_Negative_OP_9Control
SA214450Control_Positive_OP_35Control
SA214451Control_Positive_OP_19Control
SA214452Control_Positive_OP_17Control
SA214453Control_Positive_OP_16Control
SA214454Control_Negative_P-06Control
SA214455Control_Negative_P-09Control
SA214456Control_Negative_P-08Control
SA214457Control_Negative_P-10Control
SA214458Control_Negative_P-11Control
SA214459Control_Negative_P-12Control
SA214460Control_Negative_P-07Control
SA214461Control_Positive_OP_40Control
SA214462Control_Negative_P-02Control
SA214463Control_Negative_P-03Control
SA214464Control_Negative_P-04Control
SA214465Control_Negative_P-05Control
SA214466Control_Negative_P-01Control
SA214467Control_Positive_P-03Control
SA214468Control_Positive_P-14Control
SA214469Control_Negative_OP_35Control
SA214470Control_Positive_P-13Control
SA214471Control_Positive_P-12Control
SA214472Control_Positive_P-11Control
SA214473Control_Negative_OP_19Control
SA214474Control_Negative_OP_18Control
SA214475Control_Negative_OP_14Control
SA214476Control_Negative_OP_15Control
SA214477Control_Negative_OP_16Control
SA214478Control_Negative_OP_17Control
SA214479Control_Positive_P-10Control
SA214480Control_Positive_P-09Control
SA214481Control_Positive_P-02Control
SA214482Control_Positive_P-01Control
SA214483Control_Positive_OP_8Control
SA214484Control_Positive_OP_42Control
SA214485Control_Negative_P-13Control
SA214486Control_Positive_P-04Control
SA214487Control_Positive_P-08Control
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Collection:

Collection ID:CO002323
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:TR002342
Treatment Summary:NA

Sample Preparation:

Sampleprep ID:SP002336
Sampleprep Summary:20 μL plasma, was mixed with 30 μL internal standard working solution, and extracted with 200 μL methanol for 10 min, and precipitated protein at -20℃ for 1h. After centrifugation at 14000xg for 10 min at 4 ℃, the supernatant was transferred into a new tube, dried under nitrogen, and resuspended in 50 μL acetonitrile/water (75/25, v/v). 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 (30 μL) were transferred into injection vials for metabolomic analysis.

Combined analysis:

Analysis ID AN003663 AN003664
Analysis type MS MS
Chromatography type HILIC HILIC
Chromatography system Thermo Dionex Ultimate 3000 Thermo Dionex Ultimate 3000
Column Ascentis Express HILIC HPLC (150 x 2.1mm,2.7um) Ascentis Express HILIC HPLC (150 x 2.1mm,2.7um)
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:CH002714
Instrument Name:Thermo Dionex Ultimate 3000
Column Name:Ascentis Express HILIC HPLC (150 x 2.1mm,2.7um)
Column Temperature:35
Flow Gradient:10% B for 2 min, and ramped to 30% B in 8 min, and ramped to 100 % B in 5 min, and maintained at 100 % B for 3 min, and back to initial 10 % B in 1 min, and equilibrate at initial condition for 7 min.
Flow Rate:0.25 ml/min
Injection Temperature:4
Solvent A:95% acetonitrile/5% water; 0.1% acetic acid; 10 mM ammonium acetate
Solvent B:95% water/5% acetonitrile; 0.1% acetic acid; 10 mM ammonium acetate
Analytical Time:26min
Chromatography Type:HILIC

MS:

MS ID:MS003414
Analysis ID:AN003663
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. To build up metabolite spectral library for targeted analysis, we ran the pooled QC samples in full scan/ddMS2 mode (untargeted metabolomics). The Full Scan settings were as follows: AGC target, 1e6; Maximum IT, 200 ms; scan range, 60 to 900 m/z. Top 20 MS/MS spectral (dd-MS2) @ 15000 were generated with AGC target = 2e5, Maximum IT=25 ms, and (N)CE/stepped nce = 20, 30, 40v. Metabolites detection and identification were performed using Compound Discovery 2.1 (Thermo Scientific, Waltham, MA) by searching against online database (mzCloud) and in-house database built on Sigma metabolomics library (LSMLS, Sigma-Aldrich) (mzValut). Well annotated metabolites (MS spectral match and retention time match) were used to generate an inclusion list (Supplementary Table 3) for targeted PRM analysis. Final data acquisition was performed in Full scan + PRM modes. The PRM settings were as follows: resolution = 15000, AGC target = 2e5, Maximum IT=25 ms, loop count = 20, isolation window = 2.0, (N)CE was optimized for each metabolite.
Ion Mode:POSITIVE
Capillary Temperature:325
Spray Voltage:3500
  
MS ID:MS003415
Analysis ID:AN003664
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. To build up metabolite spectral library for targeted analysis, we ran the pooled QC samples in full scan/ddMS2 mode (untargeted metabolomics). The Full Scan settings were as follows: AGC target, 1e6; Maximum IT, 200 ms; scan range, 60 to 900 m/z. Top 20 MS/MS spectral (dd-MS2) @ 15000 were generated with AGC target = 2e5, Maximum IT=25 ms, and (N)CE/stepped nce = 20, 30, 40v. Metabolites detection and identification were performed using Compound Discovery 2.1 (Thermo Scientific, Waltham, MA) by searching against online database (mzCloud) and in-house database built on Sigma metabolomics library (LSMLS, Sigma-Aldrich) (mzValut). Well annotated metabolites (MS spectral match and retention time match) were used to generate an inclusion list (Supplementary Table 3) for targeted PRM analysis. Final data acquisition was performed in Full scan + PRM modes. The PRM settings were as follows: resolution = 15000, AGC target = 2e5, Maximum IT=25 ms, loop count = 20, isolation window = 2.0, (N)CE was optimized for each metabolite.
Ion Mode:NEGATIVE
Capillary Temperature:325
Spray Voltage:3000
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