[논문]Analysis of Disease Progression-Associated Gene Expression Profile in Fibrillin-1 Mutant Mice: New Insight into Molecular Pathogenesis of Marfan Syndrome

Kim, Koung Li; Choi, Chanmi; Suh, Wonhee

doi:10.4062/biomolther.2014.010

Analysis of Disease Progression-Associated Gene Expression Profile in Fibrillin-1 Mutant Mice: New Insight into Molecular Pathogenesis of Marfan Syndrome 원문보기

Biomolecules & therapeutics, v.22 no.2, 2014년, pp.143 - 148

Kim, Koung Li (College of Pharmacy, Ajou University) , Choi, Chanmi (College of Pharmacy, Ajou University) , Suh, Wonhee (College of Pharmacy, Ajou University)

Abstract ▼ AI-Helper

Marfan syndrome (MFS) is a dominantly inherited connective tissue disorder caused by mutations in the gene encoding fibrillin-1 (FBN1) and is characterized by aortic dilatation and dissection, which is the primary cause of death in untreated MFS patients. However, disease progression-associated changes in gene expression in the aortic lesions of MFS patients remained unknown. Using a mouse model of MFS, FBN1 hypomorphic mouse (mgR/mgR), we characterized the aortic gene expression profiles during the progression of the MFS. Homozygous mgR mice exhibited MFS-like phenotypic features, such as fragmentation of elastic fibers throughout the vessel wall and were graded into mgR1-4 based on the pathological severity in aortic walls. Comparative gene expression profiling of WT and four mgR mice using microarrays revealed that the changes in the transcriptome were a direct reflection of the severity of aortic pathological features. Gene ontology analysis showed that genes related to oxidation/reduction, myofibril assembly, cytoskeleton organization, and cell adhesion were differentially expressed in the mgR mice. Further analysis of differentially expressed genes identified several candidate genes whose known roles were suggestive of their involvement in the progressive destruction of aorta during MFS. This study is the first genome-wide analysis of the aortic gene expression profiles associated with the progression of MFS. Our findings provide valuable information regarding the molecular pathogenesis during MFS progression and contribute to the development of new biomarkers as well as improved therapeutic strategies.

주제어

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제안 방법

Briefly, biotinylated cDNAs were synthesized from equal amounts of total RNA. After cDNA probes were hybridized as described in the Gene Chip whole transcript sense target labeling assay manual (Affymetrix), the chips were scanned using a Genechip Array scanner 3000 7G (Affymetrix) and the scanned images were analyzed using the Affymetrix Command Console software (version1.1). Probes with p value of <0.
, 2012). However, because the disease severity did not difer among the patients whose samples were analyzed, this study failed to identify a distinct gene expression pattern that marked the progression of MFS. Additionally, gene expression profiles of skin tissues may not be relevant to the phenotypic changes of aorta.
Since the expression of the genes related to MFS pathogenesis was likely to be persistently elevated or repressed during the disease progression, we grouped 1,137 DEGs into 16 clusters according to their expression patterns by means of K-mean clustering analysis. Out of the 16 clusters, we chose five clusters that represented progressive changes in gene expression as seen in the four mgR mice and listed several genes that were likely to be associated with MFS pathogenesis (Fig.
Trizol reagent (Invitrogen) was used for the extraction of RNA from the powdered tissue. The gene expression profiling of the tissues from homozygous mgR and WT mice was performed using Affymetrix Genechip Mouse Gene 1.0 ST microarray (Affymetrix, Santa Clara, CA). Briefly, biotinylated cDNAs were synthesized from equal amounts of total RNA.

데이터처리

Comparisons of parameters between groups were made using the post-hoc Student’s t-tests for unpaired observations.

이론/모형

Data analysis was performed using the ΔΔ Ct method, and values for GAPDH were used for normalization.
Probes with p value of <0.05 were used for analysis and were normalized using the Robust Multi-array Average normalization method.

참고문헌 (24)

Attardi LD Reczek EE Cosmas C Demicco EG McCurrach ME Lowe SW Jacks T 2000 PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family Genes Dev 14 704 718 10733530

상세보기
Bharadwaj U Marin-Muller C Li M Chen C Yao Q 2011 Mesothelin confers pancreatic cancer cell resistance to TNF-alpha-induced apoptosis through Akt/PI3K/NF-kappaB activation and IL-6/Mcl-1 overexpression Mol Cancer 10 106 21880146
Chen D Zhang J Li M Rayburn ER Wang H Zhang R 2009 RYBP stabilizes p53 by modulating MDM2 EMBO Rep 10 166 172 19098711

상세보기
Chen IH Wang HH Hsieh YS Huang WC Yeh HI Chuang YJ 2013 PRSS23 is essential for the Snail-dependent endothelial-to-mesenchymal transition during valvulogenesis in zebrafish Cardiovasc Res 97 443 453 23213106

상세보기
Dietz HC Cutting GR Pyeritz RE Maslen CL Sakai LY Corson GM Puffenberger EG Hamosh A Nanthakumar EJ Curristin SM 1991 Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene Nature 352 337 339 1852208

상세보기
Gui S Yuan G Wang L Zhou L Xue Y Yu Y Zhang J Zhang M Yang Y Wang DW 2013 Wnt3a regulates proliferation, apoptosis and function of pancreatic NIT-1 beta cells via activation of IRS2/PI3K signaling J Cell Biochem 114 1488 1497 23296977

상세보기
Habashi JP Judge DP Holm TM Cohn RD Loeys BL Cooper TK Myers L Klein EC Liu G Calvi C 2006 Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome Science 312 117 121 16601194

상세보기
Kettenhofen R Hoppe J Eberhard G Seul C Ko Y Sachinidis A 2001 Regulation of Gadd45a mRNA expression in vascular smooth muscle under growth and stress conditions Cell Signal 13 787 799 11583914

상세보기
Kim KL Yang JH Song SH Kim JY Jang SY Kim JM Kim JA Sung KI Kim YW Suh YL 2013 Positive correlation between the dysregulation of transforming growth factor-beta1 and aneurysmal pathological changes in patients with Marfan syndrome Circ J 77 952 958 23291965
Kunieda T Minamino T Nishi J Tateno K Oyama T Katsuno T Miyauchi H Orimo M Okada S Takamura M 2006 Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway Circulation 114 953 960 16908765

상세보기
Matt P Schoenhoff F Habashi J Holm T Van Erp C Loch D Carlson OD Griswold BF Fu Q De Backer J 2009 Circulating transforming growth factor-beta in Marfan syndrome Circulation 120 526 532 19635970

상세보기
Murr R Loizou JI Yang YG Cuenin C Li H Wang ZQ Herceg Z 2006 Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks Nat Cell Biol 8 91 99 16341205

상세보기
Neptune ER Frischmeyer PA Arking DE Myers L Bunton TE Gayraud B Ramirez F Sakai LY Dietz HC 2003 Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome Nat Genet 33 407 411 12598898
Palombo D Maione M Cifiello BI Udini M Maggio D Lupo M 1999 Matrix metalloproteinases. Their role in degenerative chronic diseases of abdominal aorta J Cardiovasc Surg (Torino) 40 257 260
Pereira L Lee SY Gayraud B Andrikopoulos K Shapiro SD Bunton T Biery NJ Dietz HC Sakai LY Ramirez F 1999 Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1 Proc Natl Acad Sci USA 96 3819 3823 10097121

상세보기
Pyeritz RE 2000 The Marfan syndrome Annu Rev Med 51 481 510 10774478

상세보기
Radonic T de Witte P Groenink M de Waard V Lutter R van Eijk M Jansen M Timmermans J Kempers M Scholte AJ 2012 Inflammation aggravates disease severity in Marfan syndrome patients PLoS One 7 e32963 22479353

상세보기
Sanada F Taniyama Y Iekushi K Azuma J Okayama K Kusunoki H Koibuchi N Doi T Aizawa Y Morishita R 2009 Negative action of hepatocyte growth factor/c-Met system on angiotensin II signaling via ligand-dependent epithelial growth factor receptor degradation mechanism in vascular smooth muscle cells Circ Res 105 667 675 19713535

상세보기
Schwill S Seppelt P Grunhagen J Ott CE Jugold M Ruhparwar A Robinson PN Karck M Kallenbach K 2013 The fibrillin-1 hypomorphic mgR/mgR murine model of Marfan syndrome shows severe elastolysis in all segments of the aorta J Vasc Surg 57 1628 1636 23294503
Squatrito M Gorrini C Amati B 2006 Tip60 in DNA damage response and growth control: many tricks in one HAT Trends Cell Biol 16 433 442 16904321

상세보기
Wilkinson JC Richter BW Wilkinson AS Burstein E Rumble JM Balliu B Duckett CS 2004 VIAF, a conserved inhibitor of apoptosis (IAP)-interacting factor that modulates caspase activation J Biol Chem 279 51091 51099 15371430

상세보기
Yao Z Jaeger JC Ruzzo WL Morale CZ Emond M Francke U Milewicz DM Schwartz SM Mulvihill ER 2007 A Marfan syndrome gene expression phenotype in cultured skin fibroblasts BMC Genomics 8 319 17850668

상세보기
Yoneda T Imaizumi K Oono K Yui D Gomi F Katayama T Tohyama M 2001 Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress J Biol Chem 276 13935 13940 11278723

상세보기
Zhou A Ou AC Cho A Benz EJ Jr Huang SC 2008 Novel splicing factor RBM25 modulates Bcl-x pre-mRNA 5′ splice site selection Mol Cell Biol 28 5924 5936 18663000

상세보기

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