Summary of Study ST001240

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 PR000830. The data can be accessed directly via it's Project DOI: 10.21228/M8D68Q 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 IDST001240
Study TitleGlobal Metabolic Analysis Trisomy 21 - Cohort 2
Study SummaryA global metabolic analysis comparing the plasma of individuals with and without trisomy 21. Cohort 2.
Institute
University of Colorado Denver
Last NameCulp-Hill
First NameRachel
Address12801 E 17th Ave L18-9403D, Aurora, Colorado, 80045, USA
Emailrachel.hill@cuanschutz.edu
Phone303-724-5798
Submit Date2019-08-09
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2019-08-21
Release Version1
Rachel Culp-Hill Rachel Culp-Hill
https://dx.doi.org/10.21228/M8D68Q
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR000830
Project DOI:doi: 10.21228/M8D68Q
Project Title:Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors
Project Summary:Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by unknown mechanisms. We report here a large metabolomics study of plasma and cerebrospinal fluid showing that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. We demonstrate that immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, we show positive correlations among levels of IFN-inducible cytokines and KP dysregulation. Using metabolic tracing assays, we determine that IFN stimulation causes IDO1 overexpression and kynurenine overproduction in cells with T21, dependent on overexpression of IFN receptors encoded on chromosome 21. Finally, we show a mouse model of DS carrying triplication of the IFN receptors exhibits KP dysregulation. Altogether, these results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.
Institute:University of Colorado Denver
Laboratory:Linda Crnic Institute, Costello Lab, D'Alessandro Lab
Last Name:Culp-Hill
First Name:Rachel
Address:12801 E 17th Ave L18-9403D, Aurora, Colorado, 80045, USA
Email:rachel.hill@cuanschutz.edu
Phone:303-724-5798

Subject:

Subject ID:SU001308
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Age Or Age Range:0.5 - 76.5
Gender:Male and female

Factors:

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

mb_sample_id local_sample_id Cohort
SA089916HTP_4neg_D21_40D21
SA089917HTP_4neg_D21_41D21
SA089918HTP_4neg_D21_42D21
SA089919HTP_4neg_D21_39D21
SA089920HTP_4neg_D21_38D21
SA089921HTP_4neg_D21_35D21
SA089922HTP_4neg_D21_37D21
SA089923HTP_4neg_D21_43D21
SA089924HTP_4neg_D21_44D21
SA089925HTP_4neg_D21_51D21
SA089926HTP_4neg_D21_55D21
SA089927HTP_4neg_D21_49D21
SA089928HTP_4neg_D21_48D21
SA089929HTP_4neg_D21_46D21
SA089930HTP_4neg_D21_47D21
SA089931HTP_4neg_D21_34D21
SA089932HTP_4neg_D21_31D21
SA089933HTP_4neg_D21_10D21
SA089934HTP_4neg_D21_13D21
SA089935HTP_4neg_D21_16D21
SA089936HTP_4neg_D21_9D21
SA089937HTP_4neg_D21_7D21
SA089938HTP_4neg_D21_3D21
SA089939HTP_4neg_D21_6D21
SA089940HTP_4neg_D21_17D21
SA089941HTP_4neg_D21_19D21
SA089942HTP_4neg_D21_29D21
SA089943HTP_4neg_D21_56D21
SA089944HTP_4neg_D21_28D21
SA089945HTP_4neg_D21_25D21
SA089946HTP_4neg_D21_20D21
SA089947HTP_4neg_D21_22D21
SA089948HTP_4neg_D21_33D21
SA089949HTP_4neg_D21_57D21
SA089950HTP_4neg_D21_84D21
SA089951HTP_4neg_D21_86D21
SA089952HTP_4neg_D21_87D21
SA089953HTP_4neg_D21_83D21
SA089954HTP_4neg_D21_82D21
SA089955HTP_4neg_D21_80D21
SA089956HTP_4neg_D21_81D21
SA089957HTP_4neg_D21_88D21
SA089958HTP_4neg_D21_89D21
SA089959HTP_4neg_D21_97D21
SA089960HTP_4neg_D21_99D21
SA089961HTP_4neg_D21_96D21
SA089962HTP_4neg_D21_95D21
SA089963HTP_4neg_D21_91D21
SA089964HTP_4neg_D21_93D21
SA089965HTP_4neg_D21_79D21
SA089966HTP_4neg_D21_78D21
SA089967HTP_4neg_D21_62D21
SA089968HTP_4neg_D21_63D21
SA089969HTP_4neg_D21_61D21
SA089970HTP_4neg_D21_60D21
SA089971HTP_4neg_D21_58D21
SA089972HTP_4neg_D21_59D21
SA089973HTP_4neg_D21_64D21
SA089974HTP_4neg_D21_67D21
SA089975HTP_4neg_D21_74D21
SA089976HTP_4neg_D21_75D21
SA089977HTP_4neg_D21_72D21
SA089978HTP_4neg_D21_71D21
SA089979HTP_4neg_D21_68D21
SA089980HTP_4neg_D21_70D21
SA089981HTP_4pos_D21_1D21
SA089982HTP_4neg_D21_1D21
SA089983HTP_4pos_D21_51D21
SA089984HTP_4pos_D21_55D21
SA089985HTP_4pos_D21_57D21
SA089986HTP_4pos_D21_58D21
SA089987HTP_4pos_D21_49D21
SA089988HTP_4pos_D21_48D21
SA089989HTP_4pos_D21_43D21
SA089990HTP_4pos_D21_44D21
SA089991HTP_4pos_D21_46D21
SA089992HTP_4pos_D21_47D21
SA089993HTP_4pos_D21_59D21
SA089994HTP_4pos_D21_60D21
SA089995HTP_4pos_D21_70D21
SA089996HTP_4pos_D21_71D21
SA089997HTP_4pos_D21_72D21
SA089998HTP_4pos_D21_74D21
SA089999HTP_4pos_D21_68D21
SA090000HTP_4pos_D21_67D21
SA090001HTP_4pos_D21_61D21
SA090002HTP_4pos_D21_62D21
SA090003HTP_4pos_D21_63D21
SA090004HTP_4pos_D21_64D21
SA090005HTP_4pos_D21_42D21
SA090006HTP_4pos_D21_41D21
SA090007HTP_4pos_D21_16D21
SA090008HTP_4pos_D21_17D21
SA090009HTP_4pos_D21_19D21
SA090010HTP_4pos_D21_20D21
SA090011HTP_4pos_D21_13D21
SA090012HTP_4pos_D21_10D21
SA090013HTP_4pos_D21_3D21
SA090014HTP_4pos_D21_6D21
SA090015HTP_4pos_D21_7D21
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Collection:

Collection ID:CO001302
Collection Summary:All human subjects in this study were consented according to Colorado Multiple Institutional Review Board (COMIRB)-approved protocols. Written informed consent was obtained from parents or guardians of participants under the age of 18, and assent was obtained from participants over the age of 7 who were cognitively able to assent. Deidentified plasma samples for Cohort 1 were obtained from the Translational Nexus Clinical Data Registry and Biobank (University of Colorado Anschutz Medical Campus, COMIRB 08-1276). Additional plasma and WBC samples were obtained through the Crnic’s Institute Human Trisome Project (University of Colorado Anschutz Medical Campus, COMIRB 15-2170, www.trisome.org). Plasma was collected in Vacutainer tubes (EDTA–purple capped or Lithium heparin–light green capped) and stored at -80°C. Participant medical history was collected by the respective biobanks.
Sample Type:Blood (plasma)

Treatment:

Treatment ID:TR001323
Treatment Summary:N/A

Sample Preparation:

Sampleprep ID:SP001316
Sampleprep Summary:For plasma analyses, a volume of 20μL of was extracted in 480μL of ice-cold methanol:acetonitrile:water (5:3:2). Subsequently, these solutions were vortexed for 30 minutes at 4°C. Insoluble proteins were pelleted by centrifugation (10 minutes at 4°C and 12,000 g) and supernatants were collected and stored at -80°C until analysis.
Processing Storage Conditions:-80℃
Extract Storage:-80℃

Combined analysis:

Analysis ID AN002059 AN002060
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Thermo Vanquish Thermo Vanquish
Column Phenomenex Kinetex C18 (150 x 2.1mm,2.6um) Phenomenex Kinetex C18 (150 x 2.1mm,2.6um)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive Orbitrap Thermo Q Exactive Orbitrap
Ion Mode NEGATIVE POSITIVE
Units relative abundance relative abundance

Chromatography:

Chromatography ID:CH001497
Chromatography Summary:UHPLC-MS metabolomics analyses were performed using a Vanquish UHPLC system coupled online to a Q Exactive mass spectrometer (Thermo Fisher, Bremen, Germany). Samples were resolved over a Kinetex C18 column (2.1x150 mm, 1.7μm; Phenomenex, Torrance, CA, USA) at 25°C using a 3-minute isocratic flow rate at 250μL/minute at 0% B (A: 95% water/5% acetonitrile, 5mM NH4OAc) for positive mode. To monitor possible technical variability, aliquots of each of the individual samples were combined to make technical replicates, which were run after every 15 samples. Additionally, in each experiment, several lysis solution aliquots were run as blanks for artifact identification. The Q Exactive mass spectrometer (Thermo Fisher Scientific, San Jose, CA, USA) was operated in negative ion mode using electrospray ionization, scanning in Full MS mode (2μscans) from 65 to 900 m/z at 70,000 resolution, with 4 kV spray voltage, 15 sheath gas, 5 auxiliary gas. MS analysis and data elaboration were performed as described74,75. Calibration was performed prior to analysis using the PierceTM Negative Ion Calibration Solution (Thermo Fisher Scientific).
Methods Filename:4MMneg_method.pdf
Instrument Name:Thermo Vanquish
Column Name:Phenomenex Kinetex C18 (150 x 2.1mm,2.6um)
Column Temperature:45
Flow Gradient:0-100% B
Flow Rate:450uL/min
Injection Temperature:4
Solvent A:95% water/5% acetonitrile; 5 mM ammonium acetate
Solvent B:95% acetonitrile/5% water; 5 mM ammonium acetate
Analytical Time:4min
Capillary Voltage:4kV
Washing Buffer:10% methanol
Chromatography Type:Reversed phase
  
Chromatography ID:CH001498
Chromatography Summary:UHPLC-MS metabolomics analyses were performed using a Vanquish UHPLC system coupled online to a Q Exactive mass spectrometer (Thermo Fisher, Bremen, Germany). Samples were resolved over a Kinetex C18 column (2.1x150 mm, 1.7μm; Phenomenex, Torrance, CA, USA) at 45°C using a 4 minute gradient at 450μL/minute from 0-100% B (A: 95% water/5% acetonitrile, 5mM NH4OAc; B: 95% acetonitrile/5% water, 5mM NH4OAc) for negative mode. To monitor possible technical variability, aliquots of each of the individual samples were combined to make technical replicates, which were run after every 15 samples. Additionally, in each experiment, several lysis solution aliquots were run as blanks for artifact identification.
Methods Filename:4MMpos_method.pdf
Instrument Name:Thermo Vanquish
Column Name:Phenomenex Kinetex C18 (150 x 2.1mm,2.6um)
Column Temperature:45
Flow Gradient:5-95% B
Flow Rate:450uL/min
Injection Temperature:4
Solvent A:100% water; 0.1% formic acid
Solvent B:100% acetonitrile; 0.1% formic acid
Analytical Time:4min
Capillary Voltage:4kV
Washing Buffer:10% methanol
Chromatography Type:Reversed phase

MS:

MS ID:MS001910
Analysis ID:AN002059
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:The Q Exactive mass spectrometer (Thermo Fisher Scientific, San Jose, CA, USA) was operated in negative ion mode using electrospray ionization, scanning in Full MS mode (1μscan) from 65 to 975 m/z at 70,000 resolution, with 4 kV spray voltage, 45 sheath gas, 15 auxiliary gas. MS analysis and data elaboration were performed as described74,75. Calibration was performed prior to analysis using the PierceTM Negative Ion Calibration Solution (Thermo Fisher Scientific).
Ion Mode:NEGATIVE
  
MS ID:MS001911
Analysis ID:AN002060
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:The Q Exactive mass spectrometer (Thermo Fisher Scientific, San Jose, CA, USA) was operated in positive ion mode using electrospray ionization, scanning in Full MS mode (1μscan) from 65 to 975 m/z at 70,000 resolution, with 4 kV spray voltage, 45 sheath gas, 15 auxiliary gas. MS analysis and data elaboration were performed as described74,75. Calibration was performed prior to analysis using the PierceTM Positive Ion Calibration Solution (Thermo Fisher Scientific).
Ion Mode:POSITIVE
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