Summary of Study ST000419

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 PR000328. The data can be accessed directly via it's Project DOI: 10.21228/M8MK6M This work is supported by NIH grant, U2C- DK119886.

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Study IDST000419
Study TitleImpact Of High Sugar Diet On L-Arginine Metabolism In The Lung (part I)
Study SummaryAsthma is a progressive inflammatory airways disease that leads to structural airway changes and debilitating symptoms in many severely affected adults. We need novel therapeutic agents that are affordable, can decrease the reliance on steroids, and can improve quality of life. This clinical and mechanistic study has the potential to impact treatment of a subset of adult severe asthmatics and to further our understanding of the mechanisms of L-arginine metabolism and NO biology in the airways of asthmatics. We will pursue a clinical trial in subjects not well controlled on standard drug therapy; this strategy will address whether L-arginine is efficacious in patients receiving standard of care medications. In studies using animal models, we and others have shown that interventions that augment NO levels, through either supplementation of L-arginine or inhibition of arginase, decrease allergic airway inflammation and hyperresponsiveness-the two hallmarks of asthma. Overall, we hypothesize that a responder subset of adult severe asthma patients will derive clinical benefit from supplemental L-arginine therapy and that these patients will have a lower exhaled NO concentrations (<20 ppb) and a higher NOS2/Arg1 mRNA and protein ratio in their airway epithelial cells than non-responders. We aim to: 1) test the hypothesis that uncontrolled, adult severe asthma patients with exhaled breath NO concentrations <20 ppb will have fewer asthma exacerbations over 3 months when treated with L-arginine compared to patients with FeNO > 25, 2) determine the mechanisms by which L-arginine affects the regulation of NOS and arginase enzymes in primary airway epithelial cell cultures from severe asthmatic subjects, and 3) test the hypothesis that inhaled nanoparticle carrier formulations of L-arginine will decrease airway inflammation, airway hyperresponsiveness, and airway fibrosis at lower doses than systemically administered L-arginine. The major impact of our study will be to identify the adult severe asthma cohort that will benefit from supplemental L-arginine therapy. Our ultimate goal is to develop novel therapeutic agents to treat adult severe asthma patients better. PUBLIC HEALTH RELEVANCE: Asthma is a progressive inflammatory airways disease that leads to structural airway changes and debilitating symptoms in many severely affected adults. This clinical study has the potential to improve the care of adult severe asthmatics and to further our understanding of the mechanisms of L-arginine metabolism and nitric oxide biology in the lung. If we demonstrate that L-arginine supplementation can decrease asthma attacks in a subset of severe asthmatics, it will have great implications for future research as well as for the daily lives of patients with asthma.
Institute
University of California, Davis
DepartmentGenome and Biomedical Sciences Facility
LaboratoryWCMC Metabolomics Core
Last NameFiehn
First NameOliver
Address1315 Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Davis, CA 95616
Emailofiehn@ucdavis.edu
Phone(530) 754-8258
Submit Date2016-07-13
Raw Data AvailableYes
Raw Data File Type(s)peg
Analysis Type DetailGC-MS
Release Date2016-09-23
Release Version1
Oliver Fiehn Oliver Fiehn
https://dx.doi.org/10.21228/M8MK6M
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000328
Project DOI:doi: 10.21228/M8MK6M
Project Title:Impact Of High Sugar Diet On L-Arginine Metabolism In The Lung
Project Summary:Asthma is a progressive inflammatory airways disease that leads to structural airway changes and debilitating symptoms in many severely affected adults. We need novel therapeutic agents that are affordable, can decrease the reliance on steroids, and can improve quality of life. This clinical and mechanistic study has the potential to impact treatment of a subset of adult severe asthmatics and to further our understanding of the mechanisms of L-arginine metabolism and NO biology in the airways of asthmatics. We will pursue a clinical trial in subjects not well controlled on standard drug therapy; this strategy will address whether L-arginine is efficacious in patients receiving standard of care medications. In studies using animal models, we and others have shown that interventions that augment NO levels, through either supplementation of L-arginine or inhibition of arginase, decrease allergic airway inflammation and hyperresponsiveness-the two hallmarks of asthma. Overall, we hypothesize that a responder subset of adult severe asthma patients will derive clinical benefit from supplemental L-arginine therapy and that these patients will have a lower exhaled NO concentrations (<20 ppb) and a higher NOS2/Arg1 mRNA and protein ratio in their airway epithelial cells than non-responders. We aim to: 1) test the hypothesis that uncontrolled, adult severe asthma patients with exhaled breath NO concentrations <20 ppb will have fewer asthma exacerbations over 3 months when treated with L-arginine compared to patients with FeNO > 25, 2) determine the mechanisms by which L-arginine affects the regulation of NOS and arginase enzymes in primary airway epithelial cell cultures from severe asthmatic subjects, and 3) test the hypothesis that inhaled nanoparticle carrier formulations of L-arginine will decrease airway inflammation, airway hyperresponsiveness, and airway fibrosis at lower doses than systemically administered L-arginine. The major impact of our study will be to identify the adult severe asthma cohort that will benefit from supplemental L-arginine therapy. Our ultimate goal is to develop novel therapeutic agents to treat adult severe asthma patients better. PUBLIC HEALTH RELEVANCE: Asthma is a progressive inflammatory airways disease that leads to structural airway changes and debilitating symptoms in many severely affected adults. This clinical study has the potential to improve the care of adult severe asthmatics and to further our understanding of the mechanisms of L-arginine metabolism and nitric oxide biology in the lung. If we demonstrate that L-arginine supplementation can decrease asthma attacks in a subset of severe asthmatics, it will have great implications for future research as well as for the daily lives of patients with asthma.
Institute:University of California, Davis
Department:Genome and Biomedical Sciences Facility
Laboratory:WCMC Metabolomics Core
Last Name:Fiehn
First Name:Oliver
Address:1315 Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Davis, CA 95616
Email:ofiehn@ucdavis.edu
Phone:(530) 754-8258
Funding Source:NIH U24DK097154

Subject:

Subject ID:SU000440
Subject Type:Animal
Subject Species:Mus musculus
Taxonomy ID:10090
Gender:Male
Species Group:Mammal

Factors:

Subject type: Animal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Organ Diet Assignment
SA021035150129cctsa10_2Kidney Biorecs - 2
SA021036150129cctsa11_1Kidney Biorecs - 2
SA021037150128cctsa08_2Kidney Control Chow
SA021038150128cctsa13_2Kidney Control Chow
SA021039150128cctsa23_1Kidney Control Chow
SA021040150127cctsa38_1Kidney Control Chow
SA021041150128cctsa27_1Kidney Control Chow
SA021042150128cctsa29_1Kidney Control Chow
SA021043150127cctsa45_1Kidney Control Chow
SA021044150128cctsa18_2Kidney Control Chow
SA021045150128cctsa25_1Kidney Control Chow
SA021046150128cctsa19_2Kidney High Fat Chow
SA021047150128cctsa15_2Kidney High Fat Chow
SA021048150127cctsa31_1Kidney High Fat Chow
SA021049150128cctsa33_1Kidney High Fat Chow
SA021050150128cctsa11_2Kidney High Fat Chow
SA021051150128cctsa38_1Kidney High Fat Chow
SA021052150128cctsa43_1Kidney High Fat Chow
SA021053150128cctsa24_1Kidney Very High Fat Chow
SA021054150128cctsa06_2Kidney Very High Fat Chow
SA021055150128cctsa28_1Kidney Very High Fat Chow
SA021056150128cctsa12_2Kidney Very High Fat Chow
SA021057150128cctsa48_1Kidney Very High Fat Chow
SA021058150128cctsa05_3Kidney Very High Fat Chow
SA021059150127cctsa35_1Kidney Very High Fat Chow
SA021060150128cctsa39_1Kidney Very High Fat Chow
SA021061150128cctsa02_3Kidney Very High Fat Chow
SA021062150129cctsa06_1Liver Biorecs - 2
SA021063150129cctsa07_1Liver Biorecs - 2
SA021064150128cctsa04_3Liver Control Chow
SA021065150127cctsa47_1Liver Control Chow
SA021066150128cctsa14_2Liver Control Chow
SA021067150128cctsa47_1Liver Control Chow
SA021068150127cctsa46_1Liver Control Chow
SA021069150128cctsa01_3Liver Control Chow
SA021070150127cctsa30_1Liver Control Chow
SA021071150127cctsa42_1Liver Control Chow
SA021072150127cctsa49_3Liver High Fat Chow
SA021073150127cctsa50_3Liver High Fat Chow
SA021074150127cctsa33_1Liver High Fat Chow
SA021075150128cctsa41_1Liver High Fat Chow
SA021076150128cctsa03_3Liver High Fat Chow
SA021077150128cctsa34_1Liver High Fat Chow
SA021078150128cctsa36_1Liver High Fat Chow
SA021079150127cctsa32_1Liver Very High Fat Chow
SA021080150128cctsa10_2Liver Very High Fat Chow
SA021081150127cctsa43_1Liver Very High Fat Chow
SA021082150128cctsa22_1Liver Very High Fat Chow
SA021083150128cctsa37_1Liver Very High Fat Chow
SA021084150128cctsa45_1Liver Very High Fat Chow
SA021085150128cctsa17_2Liver Very High Fat Chow
SA021086150128cctsa30_1Liver Very High Fat Chow
SA021087150128cctsa35_1Liver Very High Fat Chow
SA021088150129cctsa09_2Lung Biorecs - 2
SA021089150129cctsa08_2Lung Biorecs - 2
SA021090150128cctsa09_2Lung Control Chow
SA021091150127cctsa48_1Lung Control Chow
SA021092150127cctsa41_1Lung Control Chow
SA021093150128cctsa49_1Lung Control Chow
SA021094150128cctsa44_2Lung Control Chow
SA021095150128cctsa20_1Lung Control Chow
SA021096150127cctsa29_1Lung Control Chow
SA021097150128cctsa32_1Lung Control Chow
SA021098150127cctsa34_1Lung Control Chow
SA021099150129cctsa01_1Lung High Fat Chow
SA021100150128cctsa26_1Lung High Fat Chow
SA021101150128cctsa50_1Lung High Fat Chow
SA021102150127cctsa36_1Lung High Fat Chow
SA021103150128cctsa16_2Lung High Fat Chow
SA021104150127cctsa40_1Lung High Fat Chow
SA021105150127cctsa37_1Lung High Fat Chow
SA021106150128cctsa07_2Lung High Fat Chow
SA021107150128cctsa21_1Lung Very High Fat Chow
SA021108150128cctsa31_1Lung Very High Fat Chow
SA021109150127cctsa44_1Lung Very High Fat Chow
SA021110150128cctsa42_1Lung Very High Fat Chow
SA021111150129cctsa02_1Lung Very High Fat Chow
SA021112150128cctsa46_1Lung Very High Fat Chow
SA021113150127cctsa39_1Lung Very High Fat Chow
SA021114150128cctsa40_1Lung Very High Fat Chow
Showing results 1 to 80 of 80

Collection:

Collection ID:CO000434
Collection Summary:C57BL/6 mice, 6-7 weeks of age upon diet assignment were fed for 150 days and weighed daily. Mice were euthanized with an overdose of pentobarbital IP and lungs were flash frozen. 6 mg of lung tissue was extracted for GC-TOFMS and HILIC-QTOFMS analysis.
Sample Type:Tissue

Treatment:

Treatment ID:TR000454
Treatment Summary:Male C57BL/6N mice (6-7 weeks of age) were provided ad libitum access to one of three diets for 150 days: low fat (10% kcals) control (CTRL) chow, high fat (45% kcals) with sugar (HFS) chow or very high (60% kcals) fat (VHF) chow. Body weight and food intake were measured daily.
Treatment Doseduration:150 Days

Sample Preparation:

Sampleprep ID:SP000447
Sampleprep Summary:1. Weigh 50 mg tissue sample in to a 25 ml conical polypropylene centrifuge tube. 2. Add 2.5mL extraction solvent to the tissue sample and homogenize for 45 seconds ensuring that sample resembles a powder. In between samples, clean the homogenizer in solutions of methanol, acetone, water, and the extraction solvent. 3. Centrifuge the samples at 2500 rpm. for 5 minutes. Aliquot 2 X 500μl supernatant, one for analysis and one for a backup sample. Store backup aliquot in the -20°C freezer. 4. Evaporate one 500μl aliquot of the sample in the Labconco Centrivap cold trap concentrator to complete dryness 5. The dried aliquot is then re-suspended with 500l 50% acetonitrile (degassed as given) 6. Centrifuge for 2 min at 14000 rcf using the centrifuge Eppendorf 5415. 7. Remove supernatant to a new Eppendorff tube. 8. Evaporate the supernatant to dryness in the the Labconco Centrivap cold trap concentrator. 9. Submit to derivatization.
Sampleprep Protocol Filename:SOP Extraction of Mammalian Tissue Samples.pdf

Combined analysis:

Analysis ID AN000661
Analysis type MS
Chromatography type GC
Chromatography system Leco Pegasus 4D GC
Column Restek Corporation Rtx-5Sil MS
MS Type EI
MS instrument type GC x GC-TOF
MS instrument name Leco Pegasus 4D GCxGC TOF
Ion Mode POSITIVE
Units counts

Chromatography:

Chromatography ID:CH000478
Methods Filename:Data_Dictionary_Fiehn_laboratory_GCTOF_MS_primary_metabolism_10-15-2013_general.pdf
Instrument Name:Leco Pegasus 4D GC
Column Name:Restek Corporation Rtx-5Sil MS
Column Pressure:7.7 PSI
Column Temperature:50-330C
Flow Rate:1 ml/min
Injection Temperature:50 C ramped to 250 C by 12 C/s
Sample Injection:0.5 uL
Oven Temperature:50°C for 1 min, then ramped at 20°C/min to 330°C, held constant for 5 min
Transferline Temperature:230C
Washing Buffer:Ethyl Acetate
Sample Loop Size:30 m length x 0.25 mm internal diameter
Randomization Order:Excel generated
Chromatography Type:GC

MS:

MS ID:MS000587
Analysis ID:AN000661
Instrument Name:Leco Pegasus 4D GCxGC TOF
Instrument Type:GC x GC-TOF
MS Type:EI
Ion Mode:POSITIVE
Ion Source Temperature:250 C
Ionization Energy:70 eV
Mass Accuracy:Nominal
Source Temperature:250 C
Scan Range Moverz:85-500 Da
Scanning Cycle:17 Hz
Scanning Range:85-500 Da
Skimmer Voltage:1850 V
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