Peri-arteriolar Myofibroblast Differentiation in the Pathobiology of IPAH
Peri-arteriolar Myofibroblast Differentiation in the Pathobiology of IPAH
批准号:
8335478
负责人:
ARTHUR ROGER STRAUCH
金额:
$7.63万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-09-23 至 2014-01-31
关键词:
AffectBackBiochemicalBlood VesselsBlood flowBoxingCell NucleusCellular biologyCicatrixCoagulation ProcessCollagen Type IComplexConsensusDNADNA-Binding ProteinsDNA-Protein InteractionDiagnosisDiseaseDisease ProgressionEnzyme-Linked Immunosorbent AssayEpigenetic ProcessEpithelialEpithelial CellsEtiologyFibroblastsFibrosisFosteringFunctional disorderFutureGene ActivationGene ExpressionGenesHeart failureIndividualInfarctionInfectionKnowledgeLeadLungLung TransplantationMAP2K1 geneMediatingMesenchymalMetabolicMethodsMolecularMuscleMyofibroblastObstructionOrgan TransplantationOutputPatientsPerfusionPhasePhosphotransferasesProcessProtein BiochemistryProteinsPulmonary HypertensionPulmonary artery structureResearchSerum Response FactorSideSignal TransductionSiteSmad ProteinsSmad proteinSmooth Muscle Actin Staining MethodSolidSpecimenStagingStrokeSudden DeathSyndromeTestingTissuesTrans-ActivatorsTranscription CoactivatorTranscription Repressor/CorepressorTranscriptional ActivationTraumaTunica MediaVascular DiseasesVascular remodelingWound Healingactin 2armarterial remodelingarteriolebaseblood pumpcardiopulmonary systemdesignfeedingheart functionimmunocytochemistryimprovedlung injurynew therapeutic targetnovelpromoterprotein complexpulmonary arterial hypertensionresponsetissue repairtooltreatment strategy
中文摘要
摘要
英文摘要
ABSTRACT
Idiopathic and familial syndromes of pulmonary arterial hypertension (IPAH/FPAH) typically are associated with
muscularization and obstruction of pulmonary arterial microperfusion circuits in the lung. We propose that the
pathobiology of PAH represents a dysfunctional, peri-vascular wound healing response based on a functional
deficit in the ability of the recently discovered Pur ¿ DNA-binding protein to repress TGF¿1 signaling in the
lung. Excessive transcriptional activation of wound-healing genes due to unchecked collaborative interaction
between serum response factor (SRF) and TGF¿1-regulated Smad proteins 2 and 3 results in accelerated
peri-arteriolar myofibroblast (MFB) differentiation and adventitial fibrosis with loss of pulmonary arterial
compliance and eventual right heart failure. Smads 2 and 3 normally dissociate gene-inhibitory SRF-Pur ¿
protein complexes to allow activation of the smooth muscle ¿-actin (SM¿A) and type I collagen ¿2-subunit
promoters as a first step in the MFB differentiation process. We will test the hypothesis that the SRF-Pur¿
inhibitory complex is unstable in PAH-derived MFBs due to over-active PI3K/Akt feed-forward signaling
kinases and/or impaired feed-back inhibition mediated by sub-optimal MEK1/Erk1,2/Egr-1 signaling. In Aim 1,
we propose to characterize the sub-cellular compartmentalization of transcriptional activators and repressors
implicated in peri-arteriolar myofibroblast differentiation and remodeling in IPAH/FPAH syndromes using an
immunocytochemistry approach. For Aim 2, we will define the biochemical dysfunction that causes excess
peri-arteriolar myofibroblast differentiation in IPAH/FPAH syndromes using epigenetic/metabolic approaches
that target SRF-Pur ¿ physical interplay in pulmonary artery adventitial fibroblasts isolated from normal or
disease-affected donors. We have developed solid-phase ELISA tools to quantitatively evaluate protein:protein
and protein:DNA interactions that uniquely regulate the process of adventitial MFB differentiation. The
assembly of a specialized transcriptional regulatory complex capable of triggering prototypical gene responses
in MFBs represents a convergence point for complex vascular-disease signaling consisting of multiple
compensatory and patient-specific layers of control. We expect that knowledge gained could further basic
understanding of rate-limiting interactions that foster loss of arterial compliance typically associated with the
most devastating IPAH/FPAH disease syndromes. Future detailed analysis of the protein biochemistry of
activator-repressor dynamic interplay could reveal novel targets for therapeutic management of pulmonary
arterial disease and right heart failure that may ultimately improve patient long-term survival.
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Peri-arteriolar Myofibroblast Differentiation in the Pathobiology of IPAH
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批准号:8211724
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项目类别:
-
资助金额:$7.63万
-
财政年份:2011
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负责人:ARTHUR ROGER STRAUCH
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依托单位:
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Targeting myofibroblast activation in chronic fibrotic disease
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项目类别:
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资助金额:$37.5万
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财政年份:2007
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Targeting myofibroblast activation in chronic fibrotic disease
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资助金额:$37.5万
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Myofibroblasts and fibrosis after cardiac transplant
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批准号:6659328
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财政年份:2002
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Mechanisms of Chronic Pathobiology in Allografts
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批准号:6946494
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TRANSCRIPTIONAL BASIS OF CARDIAC ALLOGRAFT REMODELING
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批准号:6184995
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TRANSCRIPTIONAL BASIS OF CARDIAC ALLOGRAFT REMODELING
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资助金额:$28.52万
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财政年份:1999
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TRANSCRIPTIONAL BASIS OF CARDIAC ALLOGRAFT REMODELING
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批准号:6638499
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资助金额:$28.76万
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TRANSCRIPTIONAL BASIS OF CARDIAC ALLOGRAFT REMODELING
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批准号:2909321
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资助金额:$29.26万
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财政年份:1999
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TRANSCRIPTIONAL BASIS OF CARDIAC ALLOGRAFT REMODELING
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资助金额:$29.37万
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财政年份:1999
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负责人:ARTHUR ROGER STRAUCH
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MOLECULAR ANATOMY OF ACTIN ASSEMBLIES IN BC3H1 CELLS
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财政年份:1990
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负责人:ARTHUR ROGER STRAUCH
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依托单位:
MOLECULAR ANATOMY OF ACTIN ASSEMBLIES IN BC3H1 CELLS
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批准号:3471270
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项目类别:
-
资助金额:$10.31万
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财政年份:1990
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负责人:ARTHUR ROGER STRAUCH
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MOLECULAR ANATOMY OF ACTIN ASSEMBLIES IN BC3H1 CELLS
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MOLECULAR ANATOMY OF ACTIN ASSEMBLIES IN BC3H1 CELLS
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MOLECULAR ANATOMY OF ACTIN ASSEMBLIES IN BC3H1 CELLS
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资助金额:$9.3万
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负责人:ARTHUR ROGER STRAUCH
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CORONARY PHENOTYPIC MODULATION AFTER CARDIAC TRANSPLANT
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CORONARY PHENOTYPIC MODULATION AFTER CARDIAC TRANSPLANT
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负责人:ARTHUR ROGER STRAUCH
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