Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model
Purpose Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary functi...
Ausführliche Beschreibung
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| Autor*in: |
Li, Huiling [verfasserIn] House, John S. [verfasserIn] Nichols, Cody E. [verfasserIn] Gruzdev, Artiom [verfasserIn] Ward, James M. [verfasserIn] Li, Jian-Liang [verfasserIn] Wyss, Annah B. [verfasserIn] Haque, Ezazul [verfasserIn] Edin, Matthew L. [verfasserIn] Elmore, Susan A. [verfasserIn] Mahler, Beth W. [verfasserIn] Degraff, Laura M. [verfasserIn] Shi, Min [verfasserIn] Zeldin, Darryl C. [verfasserIn] London, Stephanie J. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2024 |
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| Schlagwörter: |
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| Anmerkung: |
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024 |
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| Übergeordnetes Werk: |
Enthalten in: Lung - Springer US, 1903, 202(2024), 5 vom: 17. Aug., Seite 659-672 |
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| Übergeordnetes Werk: |
volume:202 ; year:2024 ; number:5 ; day:17 ; month:08 ; pages:659-672 |
| Links: |
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| DOI / URN: |
10.1007/s00408-024-00738-7 |
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| Katalog-ID: |
SPR057468230 |
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| 245 | 1 | 0 | |a Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model |
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| 500 | |a © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024 | ||
| 520 | |a Purpose Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. Methods We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. Results Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher $ FEV_{0.1} $ and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. Conclusion Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function. | ||
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| 700 | 1 | |a House, John S. |e verfasserin |4 aut | |
| 700 | 1 | |a Nichols, Cody E. |e verfasserin |4 aut | |
| 700 | 1 | |a Gruzdev, Artiom |e verfasserin |4 aut | |
| 700 | 1 | |a Ward, James M. |e verfasserin |4 aut | |
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| 700 | 1 | |a Haque, Ezazul |e verfasserin |4 aut | |
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| 700 | 1 | |a Shi, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Zeldin, Darryl C. |e verfasserin |4 aut | |
| 700 | 1 | |a London, Stephanie J. |e verfasserin |4 aut | |
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10.1007/s00408-024-00738-7 doi (DE-627)SPR057468230 (SPR)s00408-024-00738-7-e DE-627 ger DE-627 rakwb eng 610 VZ 610 VZ 44.84 bkl Li, Huiling verfasserin aut Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024 Purpose Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. Methods We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. Results Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher $ FEV_{0.1} $ and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. Conclusion Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function. Meltrin beta (dpeaa)DE-He213 RNA-Seq (dpeaa)DE-He213 Lung function (dpeaa)DE-He213 FlexiVent (dpeaa)DE-He213 Spirometry (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 House, John S. verfasserin aut Nichols, Cody E. verfasserin aut Gruzdev, Artiom verfasserin aut Ward, James M. verfasserin aut Li, Jian-Liang verfasserin aut Wyss, Annah B. verfasserin aut Haque, Ezazul verfasserin aut Edin, Matthew L. verfasserin aut Elmore, Susan A. verfasserin aut Mahler, Beth W. verfasserin aut Degraff, Laura M. verfasserin aut Shi, Min verfasserin aut Zeldin, Darryl C. verfasserin aut London, Stephanie J. verfasserin aut Enthalten in Lung Springer US, 1903 202(2024), 5 vom: 17. Aug., Seite 659-672 (DE-627)253770483 (DE-600)1459394-4 1432-1750 nnns volume:202 year:2024 number:5 day:17 month:08 pages:659-672 https://dx.doi.org/10.1007/s00408-024-00738-7 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2414 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_2574 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.84 VZ AR 202 2024 5 17 08 659-672 |
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10.1007/s00408-024-00738-7 doi (DE-627)SPR057468230 (SPR)s00408-024-00738-7-e DE-627 ger DE-627 rakwb eng 610 VZ 610 VZ 44.84 bkl Li, Huiling verfasserin aut Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024 Purpose Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. Methods We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. Results Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher $ FEV_{0.1} $ and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. Conclusion Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function. Meltrin beta (dpeaa)DE-He213 RNA-Seq (dpeaa)DE-He213 Lung function (dpeaa)DE-He213 FlexiVent (dpeaa)DE-He213 Spirometry (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 House, John S. verfasserin aut Nichols, Cody E. verfasserin aut Gruzdev, Artiom verfasserin aut Ward, James M. verfasserin aut Li, Jian-Liang verfasserin aut Wyss, Annah B. verfasserin aut Haque, Ezazul verfasserin aut Edin, Matthew L. verfasserin aut Elmore, Susan A. verfasserin aut Mahler, Beth W. verfasserin aut Degraff, Laura M. verfasserin aut Shi, Min verfasserin aut Zeldin, Darryl C. verfasserin aut London, Stephanie J. verfasserin aut Enthalten in Lung Springer US, 1903 202(2024), 5 vom: 17. Aug., Seite 659-672 (DE-627)253770483 (DE-600)1459394-4 1432-1750 nnns volume:202 year:2024 number:5 day:17 month:08 pages:659-672 https://dx.doi.org/10.1007/s00408-024-00738-7 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2414 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_2574 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.84 VZ AR 202 2024 5 17 08 659-672 |
| allfields_unstemmed |
10.1007/s00408-024-00738-7 doi (DE-627)SPR057468230 (SPR)s00408-024-00738-7-e DE-627 ger DE-627 rakwb eng 610 VZ 610 VZ 44.84 bkl Li, Huiling verfasserin aut Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024 Purpose Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. Methods We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. Results Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher $ FEV_{0.1} $ and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. Conclusion Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function. Meltrin beta (dpeaa)DE-He213 RNA-Seq (dpeaa)DE-He213 Lung function (dpeaa)DE-He213 FlexiVent (dpeaa)DE-He213 Spirometry (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 House, John S. verfasserin aut Nichols, Cody E. verfasserin aut Gruzdev, Artiom verfasserin aut Ward, James M. verfasserin aut Li, Jian-Liang verfasserin aut Wyss, Annah B. verfasserin aut Haque, Ezazul verfasserin aut Edin, Matthew L. verfasserin aut Elmore, Susan A. verfasserin aut Mahler, Beth W. verfasserin aut Degraff, Laura M. verfasserin aut Shi, Min verfasserin aut Zeldin, Darryl C. verfasserin aut London, Stephanie J. verfasserin aut Enthalten in Lung Springer US, 1903 202(2024), 5 vom: 17. Aug., Seite 659-672 (DE-627)253770483 (DE-600)1459394-4 1432-1750 nnns volume:202 year:2024 number:5 day:17 month:08 pages:659-672 https://dx.doi.org/10.1007/s00408-024-00738-7 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2414 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_2574 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.84 VZ AR 202 2024 5 17 08 659-672 |
| allfieldsGer |
10.1007/s00408-024-00738-7 doi (DE-627)SPR057468230 (SPR)s00408-024-00738-7-e DE-627 ger DE-627 rakwb eng 610 VZ 610 VZ 44.84 bkl Li, Huiling verfasserin aut Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024 Purpose Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. Methods We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. Results Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher $ FEV_{0.1} $ and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. Conclusion Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function. Meltrin beta (dpeaa)DE-He213 RNA-Seq (dpeaa)DE-He213 Lung function (dpeaa)DE-He213 FlexiVent (dpeaa)DE-He213 Spirometry (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 House, John S. verfasserin aut Nichols, Cody E. verfasserin aut Gruzdev, Artiom verfasserin aut Ward, James M. verfasserin aut Li, Jian-Liang verfasserin aut Wyss, Annah B. verfasserin aut Haque, Ezazul verfasserin aut Edin, Matthew L. verfasserin aut Elmore, Susan A. verfasserin aut Mahler, Beth W. verfasserin aut Degraff, Laura M. verfasserin aut Shi, Min verfasserin aut Zeldin, Darryl C. verfasserin aut London, Stephanie J. verfasserin aut Enthalten in Lung Springer US, 1903 202(2024), 5 vom: 17. Aug., Seite 659-672 (DE-627)253770483 (DE-600)1459394-4 1432-1750 nnns volume:202 year:2024 number:5 day:17 month:08 pages:659-672 https://dx.doi.org/10.1007/s00408-024-00738-7 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2414 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_2574 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.84 VZ AR 202 2024 5 17 08 659-672 |
| allfieldsSound |
10.1007/s00408-024-00738-7 doi (DE-627)SPR057468230 (SPR)s00408-024-00738-7-e DE-627 ger DE-627 rakwb eng 610 VZ 610 VZ 44.84 bkl Li, Huiling verfasserin aut Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024 Purpose Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. Methods We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. Results Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher $ FEV_{0.1} $ and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. Conclusion Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function. Meltrin beta (dpeaa)DE-He213 RNA-Seq (dpeaa)DE-He213 Lung function (dpeaa)DE-He213 FlexiVent (dpeaa)DE-He213 Spirometry (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 House, John S. verfasserin aut Nichols, Cody E. verfasserin aut Gruzdev, Artiom verfasserin aut Ward, James M. verfasserin aut Li, Jian-Liang verfasserin aut Wyss, Annah B. verfasserin aut Haque, Ezazul verfasserin aut Edin, Matthew L. verfasserin aut Elmore, Susan A. verfasserin aut Mahler, Beth W. verfasserin aut Degraff, Laura M. verfasserin aut Shi, Min verfasserin aut Zeldin, Darryl C. verfasserin aut London, Stephanie J. verfasserin aut Enthalten in Lung Springer US, 1903 202(2024), 5 vom: 17. Aug., Seite 659-672 (DE-627)253770483 (DE-600)1459394-4 1432-1750 nnns volume:202 year:2024 number:5 day:17 month:08 pages:659-672 https://dx.doi.org/10.1007/s00408-024-00738-7 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2414 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_2574 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.84 VZ AR 202 2024 5 17 08 659-672 |
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Enthalten in Lung 202(2024), 5 vom: 17. Aug., Seite 659-672 volume:202 year:2024 number:5 day:17 month:08 pages:659-672 |
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Enthalten in Lung 202(2024), 5 vom: 17. Aug., Seite 659-672 volume:202 year:2024 number:5 day:17 month:08 pages:659-672 |
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Meltrin beta RNA-Seq Lung function FlexiVent Spirometry Inflammation |
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Li, Huiling @@aut@@ House, John S. @@aut@@ Nichols, Cody E. @@aut@@ Gruzdev, Artiom @@aut@@ Ward, James M. @@aut@@ Li, Jian-Liang @@aut@@ Wyss, Annah B. @@aut@@ Haque, Ezazul @@aut@@ Edin, Matthew L. @@aut@@ Elmore, Susan A. @@aut@@ Mahler, Beth W. @@aut@@ Degraff, Laura M. @@aut@@ Shi, Min @@aut@@ Zeldin, Darryl C. @@aut@@ London, Stephanie J. @@aut@@ |
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2024-08-17T00:00:00Z |
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Li, Huiling |
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Li, Huiling ddc 610 bkl 44.84 misc Meltrin beta misc RNA-Seq misc Lung function misc FlexiVent misc Spirometry misc Inflammation Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model |
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610 VZ 44.84 bkl Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model Meltrin beta (dpeaa)DE-He213 RNA-Seq (dpeaa)DE-He213 Lung function (dpeaa)DE-He213 FlexiVent (dpeaa)DE-He213 Spirometry (dpeaa)DE-He213 Inflammation (dpeaa)DE-He213 |
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ddc 610 bkl 44.84 misc Meltrin beta misc RNA-Seq misc Lung function misc FlexiVent misc Spirometry misc Inflammation |
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Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model |
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Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model |
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Li, Huiling |
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Li, Huiling House, John S. Nichols, Cody E. Gruzdev, Artiom Ward, James M. Li, Jian-Liang Wyss, Annah B. Haque, Ezazul Edin, Matthew L. Elmore, Susan A. Mahler, Beth W. Degraff, Laura M. Shi, Min Zeldin, Darryl C. London, Stephanie J. |
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10.1007/s00408-024-00738-7 |
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adam19 deficiency impacts pulmonary function: human gwas follow-up in a mouse knockout model |
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Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model |
| abstract |
Purpose Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. Methods We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. Results Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher $ FEV_{0.1} $ and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. Conclusion Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function. © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024 |
| abstractGer |
Purpose Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. Methods We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. Results Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher $ FEV_{0.1} $ and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. Conclusion Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function. © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024 |
| abstract_unstemmed |
Purpose Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. Methods We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. Results Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher $ FEV_{0.1} $ and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. Conclusion Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function. © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024 |
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Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model |
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House, John S. Nichols, Cody E. Gruzdev, Artiom Ward, James M. Li, Jian-Liang Wyss, Annah B. Haque, Ezazul Edin, Matthew L. Elmore, Susan A. Mahler, Beth W. Degraff, Laura M. Shi, Min Zeldin, Darryl C. London, Stephanie J. |
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| doi_str |
10.1007/s00408-024-00738-7 |
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2024-09-27T04:50:10.367Z |
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Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. Methods We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. Results Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher $ FEV_{0.1} $ and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. 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|
| score |
7.3990917 |