Summary of study ST001242

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 IDST001242
Study TitleGlobal Metabolic Analysis Trisomy 21 - Cohort 3, CSF
Study Summaryglobal metabolic analysis of CSF 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:SU001310
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
SA090368SPIN_5neg_D21_68-L17-131D21
SA090369SPIN_5neg_D21_69-L17-170D21
SA090370SPIN_5neg_D21_67-L17-125D21
SA090371SPIN_5neg_D21_66-L17-090D21
SA090372SPIN_5neg_D21_65-L17-032D21
SA090373SPIN_5neg_D21_70-L17-207D21
SA090374SPIN_5neg_D21_71-L17-210D21
SA090375SPIN_5neg_D21_75-L17-276D21
SA090376SPIN_5neg_D21_74-L17-274D21
SA090377SPIN_5neg_D21_73-L17-246D21
SA090378SPIN_5neg_D21_72-L17-235D21
SA090379SPIN_5neg_D21_64-L16-208D21
SA090380SPIN_5neg_D21_62-L16-153D21
SA090381SPIN_5neg_D21_55-L16-048D21
SA090382SPIN_5neg_D21_56-L16-056D21
SA090383SPIN_5neg_D21_54-L16-033D21
SA090384SPIN_5neg_D21_53-L16-009D21
SA090385SPIN_5neg_D21_52-L15-195D21
SA090386SPIN_5neg_D21_57-L16-086D21
SA090387SPIN_5neg_D21_58-L16-087D21
SA090388SPIN_5neg_D21_76-L17-292D21
SA090389SPIN_5neg_D21_61-L16-146D21
SA090390SPIN_5neg_D21_60-L16-145D21
SA090391SPIN_5neg_D21_59-L16-107D21
SA090392SPIN_5neg_D21_63-L16-202D21
SA090393SPIN_5neg_D21_77-L18-020D21
SA090394SPIN_5neg_D21_93-L19-007D21
SA090395SPIN_5neg_D21_94-L19-014D21
SA090396SPIN_5neg_D21_92-L19-006D21
SA090397SPIN_5neg_D21_91-L18-342D21
SA090398SPIN_5neg_D21_90-L18-314D21
SA090399SPIN_5neg_D21_95-L19-015D21
SA090400SPIN_5neg_D21_96-L19-016D21
SA090401SPIN_5neg_D21_100-L19-114D21
SA090402SPIN_5neg_D21_99-L19-080D21
SA090403SPIN_5neg_D21_98-L19-065D21
SA090404SPIN_5neg_D21_97-L19-032D21
SA090405SPIN_5neg_D21_89-L18-303D21
SA090406SPIN_5neg_D21_88-L18-302D21
SA090407SPIN_5neg_D21_81-L18-098D21
SA090408SPIN_5neg_D21_80-L18-044D21
SA090409SPIN_5neg_D21_79-L18-028D21
SA090410SPIN_5neg_D21_78-L18-021D21
SA090411SPIN_5neg_D21_82-L18-130D21
SA090412SPIN_5neg_D21_83-L18-162D21
SA090413SPIN_5neg_D21_87-L18-238D21
SA090414SPIN_5neg_D21_86-L18-205D21
SA090415SPIN_5neg_D21_85-L18-197D21
SA090416SPIN_5neg_D21_84-L18-170D21
SA090417SPIN_5pos_D21_51-L15-181D21
SA090418SPIN_5neg_D21_51-L15-181D21
SA090419SPIN_5pos_D21_84-L18-170D21
SA090420SPIN_5pos_D21_83-L18-162D21
SA090421SPIN_5pos_D21_85-L18-197D21
SA090422SPIN_5pos_D21_86-L18-205D21
SA090423SPIN_5pos_D21_87-L18-238D21
SA090424SPIN_5pos_D21_82-L18-130D21
SA090425SPIN_5pos_D21_81-L18-098D21
SA090426SPIN_5pos_D21_77-L18-020D21
SA090427SPIN_5pos_D21_78-L18-021D21
SA090428SPIN_5pos_D21_79-L18-028D21
SA090429SPIN_5pos_D21_80-L18-044D21
SA090430SPIN_5pos_D21_88-L18-302D21
SA090431SPIN_5pos_D21_89-L18-303D21
SA090432SPIN_5pos_D21_96-L19-016D21
SA090433SPIN_5pos_D21_97-L19-032D21
SA090434SPIN_5pos_D21_98-L19-065D21
SA090435SPIN_5pos_D21_99-L19-080D21
SA090436SPIN_5pos_D21_95-L19-015D21
SA090437SPIN_5pos_D21_94-L19-014D21
SA090438SPIN_5pos_D21_90-L18-314D21
SA090439SPIN_5pos_D21_91-L18-342D21
SA090440SPIN_5pos_D21_92-L19-006D21
SA090441SPIN_5pos_D21_93-L19-007D21
SA090442SPIN_5pos_D21_75-L17-276D21
SA090443SPIN_5pos_D21_74-L17-274D21
SA090444SPIN_5pos_D21_58-L16-087D21
SA090445SPIN_5pos_D21_59-L16-107D21
SA090446SPIN_5pos_D21_60-L16-145D21
SA090447SPIN_5pos_D21_61-L16-146D21
SA090448SPIN_5pos_D21_57-L16-086D21
SA090449SPIN_5pos_D21_56-L16-056D21
SA090450SPIN_5pos_D21_52-L15-195D21
SA090451SPIN_5pos_D21_53-L16-009D21
SA090452SPIN_5pos_D21_54-L16-033D21
SA090453SPIN_5pos_D21_55-L16-048D21
SA090454SPIN_5pos_D21_62-L16-153D21
SA090455SPIN_5pos_D21_63-L16-202D21
SA090456SPIN_5pos_D21_70-L17-207D21
SA090457SPIN_5pos_D21_71-L17-210D21
SA090458SPIN_5pos_D21_72-L17-235D21
SA090459SPIN_5pos_D21_73-L17-246D21
SA090460SPIN_5pos_D21_69-L17-170D21
SA090461SPIN_5pos_D21_68-L17-131D21
SA090462SPIN_5pos_D21_64-L16-208D21
SA090463SPIN_5pos_D21_65-L17-032D21
SA090464SPIN_5pos_D21_66-L17-090D21
SA090465SPIN_5pos_D21_67-L17-125D21
SA090466SPIN_5pos_D21_100-L19-114D21
SA090467SPIN_5pos_D21_76-L17-292D21
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Collection:

Collection ID:CO001304
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:Cerebrospinal fluid

Treatment:

Treatment ID:TR001325
Treatment Summary:N/A

Sample Preparation:

Sampleprep ID:SP001318
Sampleprep Summary:For CSF analyses, a volume of 20μL of was extracted in 180μL 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 AN002063 AN002064
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:CH001501
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). 20uL of supernatant was injected for plasma and CSF samples, and 10uL of supernatant was injected for cell samples. Samples were resolved over a Kinetex C18 column (2.1x150 mm, 1.7μm; Phenomenex, Torrance, CA, USA) at 45°C using a 5-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:5MMpos_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:CH001502
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). 20uL of supernatant was injected for each sample. Samples were resolved over a Kinetex C18 column (2.1x150 mm, 1.7μm; Phenomenex, Torrance, CA, USA) at 45°C using a 5-minute gradient at 450μL/minute from 0-100% B (A: 95% water/5% acetonitrile, 1mM NH4OAc; B: 95% acetonitrile/5% water, 1mM 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:5MMneg_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:MS001914
Analysis ID:AN002063
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:MS001915
Analysis ID:AN002064
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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