An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology
Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene. Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS‐related mortality. Aberrant TGF‐beta signalling plays a m...
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| Veröffentlicht in: | Journal of cellular and molecular medicine 2019-04, Vol.23 (4), p.2526-2535 |
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| creator | Bhushan, Raghu Altinbas, Lukas Jäger, Marten Zaradzki, Marcin Lehmann, Daniel Timmermann, Bernd Clayton, Nicholas P. Zhu, Yunxiang Kallenbach, Klaus Kararigas, Georgios Robinson, Peter N. |
| description | Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene. Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS‐related mortality. Aberrant TGF‐beta signalling plays a major role in the pathophysiology of MFS. However, the contributing mechanisms are still poorly understood. Here, we aimed at identifying novel aorta‐specific pathways involved in the pathophysiology of MFS. For this purpose, we employed the Fbn1 under‐expressing mgR/mgR mouse model of MFS. We performed RNA‐sequencing of aortic tissues of 9‐week‐old mgR/mgR mice compared with wild‐type (WT) mice. With a false discovery rate |
| doi_str_mv | 10.1111/jcmm.14137 |
| format | Article |
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Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS‐related mortality. Aberrant TGF‐beta signalling plays a major role in the pathophysiology of MFS. However, the contributing mechanisms are still poorly understood. Here, we aimed at identifying novel aorta‐specific pathways involved in the pathophysiology of MFS. For this purpose, we employed the Fbn1 under‐expressing mgR/mgR mouse model of MFS. We performed RNA‐sequencing of aortic tissues of 9‐week‐old mgR/mgR mice compared with wild‐type (WT) mice. With a false discovery rate <5%, our analysis revealed 248 genes to be differentially regulated including 20 genes previously unrelated with MFS‐related pathology. Among these, we identified Igfbp2, Ccl8, Spp1, Mylk2, Mfap4, Dsp and H19. We confirmed the expression of regulated genes by quantitative real‐time PCR. Pathway classification revealed transcript signatures involved in chemokine signalling, cardiac muscle contraction, dilated and hypertrophic cardiomyopathy. Furthermore, our immunoblot analysis of aortic tissues revealed altered regulation of pSmad2 signalling, Perk1/2, Igfbp2, Mfap4, Ccl8 and Mylk2 protein levels in mgR/mgR vs WT mice. Together, our integrative systems approach identified several novel factors associated with MFS‐aortic‐specific pathophysiology that might offer potential novel therapeutic targets for MFS.</description><identifier>ISSN: 1582-1838</identifier><identifier>EISSN: 1582-4934</identifier><identifier>DOI: 10.1111/jcmm.14137</identifier><identifier>PMID: 30677223</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Aneurysms ; Animals ; Antibodies ; Aorta ; Aorta, Thoracic - metabolism ; Aorta, Thoracic - physiopathology ; Aortic dissection ; Autosomal dominant inheritance ; Cardiac muscle ; Cardiomyopathy ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Chemokine CCL8 - genetics ; Chemokine CCL8 - metabolism ; Chemokine signalling ; Chemokines ; Complications ; Coronary vessels ; Datasets ; Desmoplakins - genetics ; Desmoplakins - metabolism ; Disease Models, Animal ; eIF-2 Kinase - genetics ; eIF-2 Kinase - metabolism ; Eutrophication ; Extracellular matrix ; Extracellular Matrix Proteins - genetics ; Extracellular Matrix Proteins - metabolism ; Fibrillin ; Fibrillin-1 - deficiency ; Fibrillin-1 - genetics ; Gene Expression Regulation ; Gene Ontology ; Genes ; Genetic disorders ; Glycoproteins - genetics ; Glycoproteins - metabolism ; Hereditary diseases ; Humans ; Igfbp2 signalling ; Insulin-Like Growth Factor Binding Protein 2 - genetics ; Insulin-Like Growth Factor Binding Protein 2 - metabolism ; Insulin-like growth factor-binding protein 2 ; Kinases ; Marfan syndrome ; Marfan Syndrome - genetics ; Marfan Syndrome - metabolism ; Marfan Syndrome - physiopathology ; Mfap4 ; mgR/mgR ; Mice ; Mice, Transgenic ; Molecular Sequence Annotation ; Muscle contraction ; Muscles ; Muscular function ; Myosin-Light-Chain Kinase - genetics ; Myosin-Light-Chain Kinase - metabolism ; Original ; Osteopontin - genetics ; Osteopontin - metabolism ; Pathophysiology ; Proteins ; Ribonucleic acid ; RNA ; RNA, Long Noncoding - genetics ; RNA, Long Noncoding - metabolism ; RNA‐sequencing ; Rodents ; Signal Transduction ; Smad2 Protein - genetics ; Smad2 Protein - metabolism ; Spp1 ; Systems Biology - methods ; TGF‐beta signalling ; Therapeutic applications ; Tissues ; Transcription ; Transcriptomics</subject><ispartof>Journal of cellular and molecular medicine, 2019-04, Vol.23 (4), p.2526-2535</ispartof><rights>2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.</rights><rights>2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4767-53883b0da922addcb6e051cc07b238a12477d33469d1d817076be2774deca8db3</citedby><cites>FETCH-LOGICAL-c4767-53883b0da922addcb6e051cc07b238a12477d33469d1d817076be2774deca8db3</cites><orcidid>0000-0001-6960-6025 ; 0000-0002-8187-0176 ; 0000-0002-0736-9199</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433740/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433740/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30677223$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bhushan, Raghu</creatorcontrib><creatorcontrib>Altinbas, Lukas</creatorcontrib><creatorcontrib>Jäger, Marten</creatorcontrib><creatorcontrib>Zaradzki, Marcin</creatorcontrib><creatorcontrib>Lehmann, Daniel</creatorcontrib><creatorcontrib>Timmermann, Bernd</creatorcontrib><creatorcontrib>Clayton, Nicholas P.</creatorcontrib><creatorcontrib>Zhu, Yunxiang</creatorcontrib><creatorcontrib>Kallenbach, Klaus</creatorcontrib><creatorcontrib>Kararigas, Georgios</creatorcontrib><creatorcontrib>Robinson, Peter N.</creatorcontrib><title>An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology</title><title>Journal of cellular and molecular medicine</title><addtitle>J Cell Mol Med</addtitle><description>Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene. Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS‐related mortality. Aberrant TGF‐beta signalling plays a major role in the pathophysiology of MFS. However, the contributing mechanisms are still poorly understood. Here, we aimed at identifying novel aorta‐specific pathways involved in the pathophysiology of MFS. For this purpose, we employed the Fbn1 under‐expressing mgR/mgR mouse model of MFS. We performed RNA‐sequencing of aortic tissues of 9‐week‐old mgR/mgR mice compared with wild‐type (WT) mice. With a false discovery rate <5%, our analysis revealed 248 genes to be differentially regulated including 20 genes previously unrelated with MFS‐related pathology. Among these, we identified Igfbp2, Ccl8, Spp1, Mylk2, Mfap4, Dsp and H19. We confirmed the expression of regulated genes by quantitative real‐time PCR. Pathway classification revealed transcript signatures involved in chemokine signalling, cardiac muscle contraction, dilated and hypertrophic cardiomyopathy. Furthermore, our immunoblot analysis of aortic tissues revealed altered regulation of pSmad2 signalling, Perk1/2, Igfbp2, Mfap4, Ccl8 and Mylk2 protein levels in mgR/mgR vs WT mice. Together, our integrative systems approach identified several novel factors associated with MFS‐aortic‐specific pathophysiology that might offer potential novel therapeutic targets for MFS.</description><subject>Aneurysms</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Aorta</subject><subject>Aorta, Thoracic - metabolism</subject><subject>Aorta, Thoracic - physiopathology</subject><subject>Aortic dissection</subject><subject>Autosomal dominant inheritance</subject><subject>Cardiac muscle</subject><subject>Cardiomyopathy</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Chemokine CCL8 - genetics</subject><subject>Chemokine CCL8 - metabolism</subject><subject>Chemokine signalling</subject><subject>Chemokines</subject><subject>Complications</subject><subject>Coronary vessels</subject><subject>Datasets</subject><subject>Desmoplakins - genetics</subject><subject>Desmoplakins - metabolism</subject><subject>Disease Models, Animal</subject><subject>eIF-2 Kinase - genetics</subject><subject>eIF-2 Kinase - metabolism</subject><subject>Eutrophication</subject><subject>Extracellular matrix</subject><subject>Extracellular Matrix Proteins - genetics</subject><subject>Extracellular Matrix Proteins - metabolism</subject><subject>Fibrillin</subject><subject>Fibrillin-1 - deficiency</subject><subject>Fibrillin-1 - genetics</subject><subject>Gene Expression Regulation</subject><subject>Gene Ontology</subject><subject>Genes</subject><subject>Genetic disorders</subject><subject>Glycoproteins - genetics</subject><subject>Glycoproteins - metabolism</subject><subject>Hereditary diseases</subject><subject>Humans</subject><subject>Igfbp2 signalling</subject><subject>Insulin-Like Growth Factor Binding Protein 2 - genetics</subject><subject>Insulin-Like Growth Factor Binding Protein 2 - metabolism</subject><subject>Insulin-like growth factor-binding protein 2</subject><subject>Kinases</subject><subject>Marfan syndrome</subject><subject>Marfan Syndrome - genetics</subject><subject>Marfan Syndrome - metabolism</subject><subject>Marfan Syndrome - physiopathology</subject><subject>Mfap4</subject><subject>mgR/mgR</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Molecular Sequence Annotation</subject><subject>Muscle contraction</subject><subject>Muscles</subject><subject>Muscular function</subject><subject>Myosin-Light-Chain Kinase - genetics</subject><subject>Myosin-Light-Chain Kinase - metabolism</subject><subject>Original</subject><subject>Osteopontin - genetics</subject><subject>Osteopontin - metabolism</subject><subject>Pathophysiology</subject><subject>Proteins</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Long Noncoding - genetics</subject><subject>RNA, Long Noncoding - metabolism</subject><subject>RNA‐sequencing</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Smad2 Protein - genetics</subject><subject>Smad2 Protein - metabolism</subject><subject>Spp1</subject><subject>Systems Biology - 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metabolism</topic><topic>Aorta, Thoracic - physiopathology</topic><topic>Aortic dissection</topic><topic>Autosomal dominant inheritance</topic><topic>Cardiac muscle</topic><topic>Cardiomyopathy</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Chemokine CCL8 - genetics</topic><topic>Chemokine CCL8 - metabolism</topic><topic>Chemokine signalling</topic><topic>Chemokines</topic><topic>Complications</topic><topic>Coronary vessels</topic><topic>Datasets</topic><topic>Desmoplakins - genetics</topic><topic>Desmoplakins - metabolism</topic><topic>Disease Models, Animal</topic><topic>eIF-2 Kinase - genetics</topic><topic>eIF-2 Kinase - metabolism</topic><topic>Eutrophication</topic><topic>Extracellular matrix</topic><topic>Extracellular Matrix Proteins - genetics</topic><topic>Extracellular Matrix Proteins - metabolism</topic><topic>Fibrillin</topic><topic>Fibrillin-1 - deficiency</topic><topic>Fibrillin-1 - genetics</topic><topic>Gene Expression Regulation</topic><topic>Gene Ontology</topic><topic>Genes</topic><topic>Genetic disorders</topic><topic>Glycoproteins - genetics</topic><topic>Glycoproteins - metabolism</topic><topic>Hereditary diseases</topic><topic>Humans</topic><topic>Igfbp2 signalling</topic><topic>Insulin-Like Growth Factor Binding Protein 2 - genetics</topic><topic>Insulin-Like Growth Factor Binding Protein 2 - metabolism</topic><topic>Insulin-like growth factor-binding protein 2</topic><topic>Kinases</topic><topic>Marfan syndrome</topic><topic>Marfan Syndrome - genetics</topic><topic>Marfan Syndrome - metabolism</topic><topic>Marfan Syndrome - physiopathology</topic><topic>Mfap4</topic><topic>mgR/mgR</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Molecular Sequence Annotation</topic><topic>Muscle contraction</topic><topic>Muscles</topic><topic>Muscular function</topic><topic>Myosin-Light-Chain Kinase - genetics</topic><topic>Myosin-Light-Chain Kinase - metabolism</topic><topic>Original</topic><topic>Osteopontin - genetics</topic><topic>Osteopontin - metabolism</topic><topic>Pathophysiology</topic><topic>Proteins</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Long Noncoding - genetics</topic><topic>RNA, Long Noncoding - metabolism</topic><topic>RNA‐sequencing</topic><topic>Rodents</topic><topic>Signal Transduction</topic><topic>Smad2 Protein - genetics</topic><topic>Smad2 Protein - metabolism</topic><topic>Spp1</topic><topic>Systems Biology - methods</topic><topic>TGF‐beta signalling</topic><topic>Therapeutic applications</topic><topic>Tissues</topic><topic>Transcription</topic><topic>Transcriptomics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bhushan, Raghu</creatorcontrib><creatorcontrib>Altinbas, Lukas</creatorcontrib><creatorcontrib>Jäger, Marten</creatorcontrib><creatorcontrib>Zaradzki, Marcin</creatorcontrib><creatorcontrib>Lehmann, Daniel</creatorcontrib><creatorcontrib>Timmermann, Bernd</creatorcontrib><creatorcontrib>Clayton, Nicholas P.</creatorcontrib><creatorcontrib>Zhu, Yunxiang</creatorcontrib><creatorcontrib>Kallenbach, Klaus</creatorcontrib><creatorcontrib>Kararigas, Georgios</creatorcontrib><creatorcontrib>Robinson, Peter N.</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database (ProQuest)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cellular and molecular medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bhushan, Raghu</au><au>Altinbas, Lukas</au><au>Jäger, Marten</au><au>Zaradzki, Marcin</au><au>Lehmann, Daniel</au><au>Timmermann, Bernd</au><au>Clayton, Nicholas P.</au><au>Zhu, Yunxiang</au><au>Kallenbach, Klaus</au><au>Kararigas, Georgios</au><au>Robinson, Peter N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology</atitle><jtitle>Journal of cellular and molecular medicine</jtitle><addtitle>J Cell Mol Med</addtitle><date>2019-04</date><risdate>2019</risdate><volume>23</volume><issue>4</issue><spage>2526</spage><epage>2535</epage><pages>2526-2535</pages><issn>1582-1838</issn><eissn>1582-4934</eissn><abstract>Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene. Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS‐related mortality. Aberrant TGF‐beta signalling plays a major role in the pathophysiology of MFS. However, the contributing mechanisms are still poorly understood. Here, we aimed at identifying novel aorta‐specific pathways involved in the pathophysiology of MFS. For this purpose, we employed the Fbn1 under‐expressing mgR/mgR mouse model of MFS. We performed RNA‐sequencing of aortic tissues of 9‐week‐old mgR/mgR mice compared with wild‐type (WT) mice. With a false discovery rate <5%, our analysis revealed 248 genes to be differentially regulated including 20 genes previously unrelated with MFS‐related pathology. Among these, we identified Igfbp2, Ccl8, Spp1, Mylk2, Mfap4, Dsp and H19. We confirmed the expression of regulated genes by quantitative real‐time PCR. Pathway classification revealed transcript signatures involved in chemokine signalling, cardiac muscle contraction, dilated and hypertrophic cardiomyopathy. Furthermore, our immunoblot analysis of aortic tissues revealed altered regulation of pSmad2 signalling, Perk1/2, Igfbp2, Mfap4, Ccl8 and Mylk2 protein levels in mgR/mgR vs WT mice. Together, our integrative systems approach identified several novel factors associated with MFS‐aortic‐specific pathophysiology that might offer potential novel therapeutic targets for MFS.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>30677223</pmid><doi>10.1111/jcmm.14137</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-6960-6025</orcidid><orcidid>https://orcid.org/0000-0002-8187-0176</orcidid><orcidid>https://orcid.org/0000-0002-0736-9199</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6433740 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Wiley Online Library Journals Frontfile Complete; Wiley-Blackwell Open Access Titles; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Aneurysms Animals Antibodies Aorta Aorta, Thoracic - metabolism Aorta, Thoracic - physiopathology Aortic dissection Autosomal dominant inheritance Cardiac muscle Cardiomyopathy Carrier Proteins - genetics Carrier Proteins - metabolism Chemokine CCL8 - genetics Chemokine CCL8 - metabolism Chemokine signalling Chemokines Complications Coronary vessels Datasets Desmoplakins - genetics Desmoplakins - metabolism Disease Models, Animal eIF-2 Kinase - genetics eIF-2 Kinase - metabolism Eutrophication Extracellular matrix Extracellular Matrix Proteins - genetics Extracellular Matrix Proteins - metabolism Fibrillin Fibrillin-1 - deficiency Fibrillin-1 - genetics Gene Expression Regulation Gene Ontology Genes Genetic disorders Glycoproteins - genetics Glycoproteins - metabolism Hereditary diseases Humans Igfbp2 signalling Insulin-Like Growth Factor Binding Protein 2 - genetics Insulin-Like Growth Factor Binding Protein 2 - metabolism Insulin-like growth factor-binding protein 2 Kinases Marfan syndrome Marfan Syndrome - genetics Marfan Syndrome - metabolism Marfan Syndrome - physiopathology Mfap4 mgR/mgR Mice Mice, Transgenic Molecular Sequence Annotation Muscle contraction Muscles Muscular function Myosin-Light-Chain Kinase - genetics Myosin-Light-Chain Kinase - metabolism Original Osteopontin - genetics Osteopontin - metabolism Pathophysiology Proteins Ribonucleic acid RNA RNA, Long Noncoding - genetics RNA, Long Noncoding - metabolism RNA‐sequencing Rodents Signal Transduction Smad2 Protein - genetics Smad2 Protein - metabolism Spp1 Systems Biology - methods TGF‐beta signalling Therapeutic applications Tissues Transcription Transcriptomics |
| title | An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-06T16%3A13%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=An%20integrative%20systems%20approach%20identifies%20novel%20candidates%20in%20Marfan%20syndrome%E2%80%90related%20pathophysiology&rft.jtitle=Journal%20of%20cellular%20and%20molecular%20medicine&rft.au=Bhushan,%20Raghu&rft.date=2019-04&rft.volume=23&rft.issue=4&rft.spage=2526&rft.epage=2535&rft.pages=2526-2535&rft.issn=1582-1838&rft.eissn=1582-4934&rft_id=info:doi/10.1111/jcmm.14137&rft_dat=%3Cproquest_pubme%3E2179435806%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2197020984&rft_id=info:pmid/30677223&rfr_iscdi=true |