Summary of study ST001243

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 IDST001243
Study TitleGlobal Metabolic Analysis Trisomy 21 - Cohort 1
Study SummaryGlobal metabolic analysis of plasma from individuals with and without trisomy 21.
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 Date2019-08-13
Raw Data AvailableYes
Raw Data File Type(s).raw
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

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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:SU001311
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
SA090568Nexus_D21_4neg-51D21
SA090569Nexus_D21_4neg-60D21
SA090570Nexus_D21_4neg-45D21
SA090571Nexus_D21_4neg-44D21
SA090572Nexus_D21_4neg-42D21
SA090573Nexus_D21_4neg-63D21
SA090574Nexus_D21_4neg-64D21
SA090575Nexus_D21_4neg-68D21
SA090576Nexus_D21_4neg-67D21
SA090577Nexus_D21_4neg-66D21
SA090578Nexus_D21_4neg-65D21
SA090579Nexus_D21_4neg-41D21
SA090580Nexus_D21_4neg-38D21
SA090581Nexus_D21_4neg-17D21
SA090582Nexus_D21_4neg-16D21
SA090583Nexus_D21_4neg-15D21
SA090584Nexus_D21_4neg-8D21
SA090585Nexus_D21_4neg-19D21
SA090586Nexus_D21_4neg-20D21
SA090587Nexus_D21_4neg-36D21
SA090588Nexus_D21_4neg-35D21
SA090589Nexus_D21_4neg-32D21
SA090590Nexus_D21_4neg-31D21
SA090591Nexus_D21_4neg-71D21
SA090592Nexus_D21_4neg-72D21
SA090593Nexus_D21_4neg-89D21
SA090594Nexus_D21_4neg-88D21
SA090595Nexus_D21_4neg-87D21
SA090596Nexus_D21_4neg-86D21
SA090597Nexus_D21_4neg-90D21
SA090598Nexus_D21_4neg-91D21
SA090599Nexus_D21_4neg-98D21
SA090600Nexus_D21_4neg-96D21
SA090601Nexus_D21_4neg-95D21
SA090602Nexus_D21_4neg-93D21
SA090603Nexus_D21_4neg-85D21
SA090604Nexus_D21_4neg-84D21
SA090605Nexus_D21_4neg-76D21
SA090606Nexus_D21_4neg-75D21
SA090607Nexus_D21_4neg-74D21
SA090608Nexus_D21_4neg-73D21
SA090609Nexus_D21_4neg-77D21
SA090610Nexus_D21_4neg-78D21
SA090611Nexus_D21_4neg-83D21
SA090612Nexus_D21_4neg-82D21
SA090613Nexus_D21_4neg-80D21
SA090614Nexus_D21_4neg-79D21
SA090615Nexus_D21_4pos-4D21
SA090616Nexus_D21_4neg-4D21
SA090617Nexus_D21_4pos-78D21
SA090618Nexus_D21_4pos-79D21
SA090619Nexus_D21_4pos-80D21
SA090620Nexus_D21_4pos-82D21
SA090621Nexus_D21_4pos-77D21
SA090622Nexus_D21_4pos-76D21
SA090623Nexus_D21_4pos-72D21
SA090624Nexus_D21_4pos-73D21
SA090625Nexus_D21_4pos-74D21
SA090626Nexus_D21_4pos-75D21
SA090627Nexus_D21_4pos-83D21
SA090628Nexus_D21_4pos-84D21
SA090629Nexus_D21_4pos-91D21
SA090630Nexus_D21_4pos-93D21
SA090631Nexus_D21_4pos-95D21
SA090632Nexus_D21_4pos-96D21
SA090633Nexus_D21_4pos-90D21
SA090634Nexus_D21_4pos-89D21
SA090635Nexus_D21_4pos-85D21
SA090636Nexus_D21_4pos-86D21
SA090637Nexus_D21_4pos-87D21
SA090638Nexus_D21_4pos-88D21
SA090639Nexus_D21_4pos-68D21
SA090640Nexus_D21_4pos-67D21
SA090641Nexus_D21_4pos-31D21
SA090642Nexus_D21_4pos-32D21
SA090643Nexus_D21_4pos-35D21
SA090644Nexus_D21_4pos-36D21
SA090645Nexus_D21_4pos-20D21
SA090646Nexus_D21_4pos-19D21
SA090647Nexus_D21_4pos-8D21
SA090648Nexus_D21_4pos-15D21
SA090649Nexus_D21_4pos-16D21
SA090650Nexus_D21_4pos-17D21
SA090651Nexus_D21_4pos-38D21
SA090652Nexus_D21_4pos-41D21
SA090653Nexus_D21_4pos-63D21
SA090654Nexus_D21_4pos-64D21
SA090655Nexus_D21_4pos-65D21
SA090656Nexus_D21_4pos-66D21
SA090657Nexus_D21_4pos-60D21
SA090658Nexus_D21_4pos-51D21
SA090659Nexus_D21_4pos-42D21
SA090660Nexus_D21_4pos-44D21
SA090661Nexus_D21_4pos-45D21
SA090662Nexus_D21_4pos-98D21
SA090663Nexus_D21_4pos-71D21
SA090664Nexus_T21_4neg-26T21
SA090665Nexus_T21_4neg-27T21
SA090666Nexus_T21_4neg-25T21
SA090667Nexus_T21_4neg-24T21
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Collection:

Collection ID:CO001305
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:TR001326
Treatment Summary:N/A

Sample Preparation:

Sampleprep ID:SP001319
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. For quantitative analysis of kynurenine pathway (KP) metabolites, supernatants were spun in a Speedvac until dry and resuspended in 0.1% formic acid in water as previously described (PMID: 30213797, 30143553).

Combined analysis:

Analysis ID AN002065 AN002066
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Thermo Vanquish Thermo Vanquish
Column Phenomenex Kinetex C18 (150 x 2.1mm, 2.6 um) Phenomenex Kinetex C18 (150 x 2.1mm, 2.6 um)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive Orbitrap Thermo Q Exactive Orbitrap
Ion Mode POSITIVE NEGATIVE
Units relative abundance relative abundance

Chromatography:

Chromatography ID:CH001503
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 5-95% B (A: water/0.1% formic acid; B: acetonitrile/0.1% formic acid) 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.
Methods Filename:4MMpos_method.pdf
Instrument Name:Thermo Vanquish
Column Name:Phenomenex Kinetex C18 (150 x 2.1mm, 2.6 um)
Column Temperature:45
Flow Gradient:5-95% B
Flow Rate:450uL/min
Solvent A:water, 0.1% formic acid
Solvent B:acetonitrile, 0.1% formic acid
Chromatography Type:Reversed phase
  
Chromatography ID:CH001504
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:4MMneg_method.pdf
Instrument Name:Thermo Vanquish
Column Name:Phenomenex Kinetex C18 (150 x 2.1mm, 2.6 um)
Column Temperature:45
Flow Gradient:0-100% B
Flow Rate:450uL/min
Solvent A:95% water/5% acetonitrile, 1mM NH4OAc
Solvent B:95% acetonitrile/5% water, 1mM NH4OAc
Chromatography Type:Reversed phase

MS:

MS ID:MS001916
Analysis ID:AN002065
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
  
MS ID:MS001917
Analysis ID:AN002066
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
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