PlGF-HIF1a-miRNA Axis in Sickle Pulmonary Hypertension
PlGF-HIF1a-miRNA Axis in Sickle Pulmonary Hypertension
批准号:
9040244
负责人:
VIJAY K. KALRA
金额:
$61.86万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-01-01 至 2018-12-31
关键词:
3&apos Untranslated RegionsAddressAdenovirus VectorBindingBiological AvailabilityBiological MarkersCellsCessation of lifeChronicClinicalCoronary arteryDeath RateDevelopmentDiagnosisDiseaseEctopic ExpressionEmbolismEndothelial CellsEndothelin-1Erythroid CellsEthanolGenesGeneticGenetic PolymorphismGenetic TranscriptionGrowthHemolysisHumanHypoxiaIn SituInflammationIntronsKnockout MiceKnowledgeLaboratoriesLentivirus VectorLungMediatingMessenger RNAMicroRNAsMorbidity - disease rateMusNitric OxideOdds RatioPathogenesisPatientsPlacental Growth FactorPlasmaPlasminogen Activator Inhibitor 1PlayPost-Transcriptional RegulationProductionPulmonary FibrosisPulmonary HypertensionPulmonary artery structurePulmonary vesselsRNA-Binding ProteinsRegulationRiskRoleSickle Cell AnemiaSmooth MuscleSymptomsTestingTherapeuticThrombosisTranscriptTransgenic OrganismsTranslationsVascular DiseasesVascular remodelingVasoconstrictor AgentsWild Type Mousedosagehypoxia inducible factor 1in vivoknock-downlocked nucleic acidmortalitymouse modelnew therapeutic targetnovel diagnosticspre-miRNApressuresickle erythroidsicklingtranscription factor
中文摘要
项目摘要
肺动脉高压(PHT)发生在约30%的镰状细胞贫血(SCA)患者中,
诊断后2年内死亡。这种血管病变的发病机制可能是多因素的,
溶血诱导的一氧化氮生物利用度受损,促凝血剂引起的慢性血栓栓塞
状态,并增加内皮素-1(ET-1)。我们的研究表明,胎盘生长因子(PlGF)是一种
镰状红细胞产生大量的血管生成生长因子,诱导表达强效的
肺血管收缩剂ET-1和促凝血剂纤溶酶原激活物抑制剂PAI-1
肺微血管内皮细胞(HPMVEC)。PlGF通过抑制ET-1和PAI-1的表达而增加ET-1和PAI-1的表达。
诱导缺氧诱导因子-1(HIF-1)。异位PlGF可在实验上诱发PHT
在以ET-1增加为特征的正常小鼠中的表达,如在转基因镰状小鼠中观察到的,
SCA患者。我们最近观察到,在HPMVEC中,PlGF介导的HIF-1和PAI-1的诱导作用是在
在转录水平上,它们由三种特定的microRNA(miRs)调控。关于后记,人们知之甚少。
HIF-1a、ET-1和PAI-1或RNA结合蛋白的转录、miR介导的调节表达
稳定这些促进PHT基因的mRNA。因此,我们的总体假设是,
RNA结合蛋白和miRNAs改变HIF-1、ET-1和PAI-1 mRNA的稳定性,并直接影响HIF-1、ET-1和PAI-1的表达。
参与PHT的发展。为了解决这个假设,在目标1中,我们将确定后-
调节PlGF介导的HIF-1a、ET-1和PAI-1表达的转录机制,并鉴定
RNA结合蛋白和参与结合mRNA 3'UTR从而调节mRNA翻译的特异性miR
HIF-1a、ET-1和PAI-1 mRNA。在目标2中,我们将确定调节PAI-1的miR基因是否
SKA2基因是从NFYC共合成的,
SKA2初级转录物,或从较小的前体miRNA转录单位独立转录。在aim中
3,我们将证明这些miRs在HIF-1、ET-1和PAI-1的遗传调节中的需要,
过表达PlGF并发展PHT的小鼠模型。最后,我们将确定等离子体的关联
在有和没有PHT症状的SCA患者中,这些miRNA水平与血浆PlGF、ET-1和PAI-1相关。
这些研究将推进我们对RNA结合蛋白和miR如何调节一些关键的细胞因子的认识。
参与镰状PHT的基因,以及这些miRNA的表达本身是如何调节的。这些研究可能会
提供了用于评估PHT的新的诊断生物标志物,以及用于
目前几乎没有或没有治疗选择。
英文摘要
Project Summary
Pulmonary hypertension (PHT) occurs in ~30% of patients with sickle cell anemia (SCA) and results in ~50%
mortality within 2 years of diagnosis. The pathogenesis of this vasculopathy is likely multi-factorial, potentiated
by hemolysis-induced impaired nitric oxide bioavailability, chronic thrombo-embolism from a procoagulant
state, and increased endothelin-1 (ET-1). Our studies have shown that placenta growth factor (PlGF), an
angiogenic growth factor produced in high amounts by sickle erythroid cells, induces expression of the potent
pulmonary vasoconstrictor ET-1, and a procoagulant, plasminogen activator inhibitor-1 (PAI-1), from human
pulmonary microvascular endothelial cells (HPMVEC). PlGF increases ET-1 and PAI-1 expression via
induction of hypoxia-inducible factor-1¿ (HIF-1¿). PHT can be induced experimentally by ectopic PlGF
expression in normal mice characterized by increased ET-1, as is observed in transgenic sickle mice and in
SCA patients. We recently observed that PlGF-mediated induction of HIF-1¿ and PAI-1 in HPMVEC is post-
transcriptionally regulated by three specific microRNAs (miRs). Relatively little is known of the post-
transcriptional, miR-mediated, regulated expression of HIF-1a, ET-1 and PAI-1, or of the RNA-binding proteins
that stabilize the mRNAs of these genes that promote PHT. Thus our overall hypothesis is that cytoplasmic
RNA-binding proteins and miRNAs alter the stability of HIF-1¿, ET-1, and PAI-1 mRNAs, and are directly
involved in the development of PHT. To address this hypothesis, in Aim 1, we will determine the post-
transcriptional mechanisms which regulate PlGF-mediated expression of HIF-1a, ET-1 and PAI-1 and identify
RNA binding proteins and the specific miRs involved in binding to mRNA 3'UTRs thus regulating translation of
HIF-1a, ET-1, and PAI-1 mRNAs. In Aim 2, we will determine whether the genes for miRs that regulate PAI-1
expression, and are located within introns of NFYC and SKA2 genes are co-synthesized from the NFYC and
SKA2 primary transcripts, or are independently transcribed from a smaller, pre-miRNA transcription unit. In Aim
3, we will demonstrate the requirement of these miRs in the regulation of HIF-1¿, ET-1 and PAI-1 in genetic
mouse models that over-express PlGF and develop PHT. Finally, we will determine the association of plasma
levels of these miRNAs to plasma PlGF, ET-1 and PAI-1 in SCA patients with and without PHT symptoms.
These studies will advance our knowledge as to how RNA binding proteins and miRs regulate some of the key
genes involved in sickle PHT, and how expression of these miRNAs is itself regulated. These studies will likely
provide new diagnostic bio-markers for assessment of PHT, and novel therapeutic targets for a disease that
currently has few or no therapeutic options.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1161/jaha.114.000968
发表时间:
2014-05-16
期刊:
Journal of the American Heart Association
影响因子:
5.4
作者:
[Ferreira R, Santos T, Amar A, Gong A, Chen TC, Tahara SM, Giannotta SL, Hofman FM]
通讯作者:
Hofman FM
PlGF-HIF1a-miRNA Axis in Sickle Pulmonary Hypertension
-
批准号:8403676
-
项目类别:
-
资助金额:$58.68万
-
财政年份:2012
-
负责人:VIJAY K. KALRA
-
依托单位:
PlGF-HIF1a-miRNA Axis in Sickle Pulmonary Hypertension
-
批准号:8600723
-
项目类别:
-
资助金额:$60.46万
-
财政年份:2012
-
负责人:VIJAY K. KALRA
-
依托单位:
PlGF-HIF1a-miRNA Axis in Sickle Pulmonary Hypertension
-
批准号:8219269
-
项目类别:
-
资助金额:$63.51万
-
财政年份:2012
-
负责人:VIJAY K. KALRA
-
依托单位:
ROLE OF ENDOTHELIN-1 INSICKLEACUTE CHEST SYNDROME
-
批准号:7001823
-
项目类别:
-
资助金额:$33.89万
-
财政年份:2004
-
负责人:VIJAY K. KALRA
-
依托单位:
ENDOTHELIAL DYSFUNCTION AND VASOOCCLUSION IN SICKLE CELL ANEMIA
-
批准号:6667525
-
项目类别:
-
资助金额:$49.81万
-
财政年份:2002
-
负责人:VIJAY K. KALRA
-
依托单位:
ENDOTHELIAL DYSFUNCTION AND VASOOCCLUSION IN SICKLE CELL ANEMIA
-
批准号:6646660
-
项目类别:
-
资助金额:$49.81万
-
财政年份:2002
-
负责人:VIJAY K. KALRA
-
依托单位:
ENDOTHELIAL DYSFUNCTION AND VASOOCCLUSION IN SICKLE CELL ANEMIA
-
批准号:6589046
-
项目类别:
-
资助金额:$49.81万
-
财政年份:2002
-
负责人:VIJAY K. KALRA
-
依托单位:
ENDOTHELIAL DYSFUNCTION AND VASOOCCLUSION IN SICKLE CELL ANEMIA
-
批准号:6448211
-
项目类别:
-
资助金额:$49.81万
-
财政年份:2001
-
负责人:VIJAY K. KALRA
-
依托单位:
ENDOTHELIAL DYSFUNCTION AND VASOOCCLUSION IN SICKLE CELL ANEMIA
-
批准号:6325950
-
项目类别:
-
资助金额:$23.32万
-
财政年份:2000
-
负责人:VIJAY K. KALRA
-
依托单位:
AGING, AMYLOID B PEPTIDE AND MIGRATION OF MONOCYTES ACROSS THE VASCULAR WALL
-
批准号:6355549
-
项目类别:
-
资助金额:$20.93万
-
财政年份:2000
-
负责人:VIJAY K. KALRA
-
依托单位:
ENDOTHELIAL DYSFUNCTION AND VASOOCCLUSION IN SICKLE CELL ANEMIA
-
批准号:6110148
-
项目类别:
-
资助金额:$23.32万
-
财政年份:1999
-
负责人:VIJAY K. KALRA
-
依托单位:
AGING, AMYLOID B PEPTIDE AND MIGRATION OF MONOCYTES ACROSS THE VASCULAR WALL
-
批准号:6098832
-
项目类别:
-
资助金额:$20.93万
-
财政年份:1999
-
负责人:VIJAY K. KALRA
-
依托单位:
ENDOTHELIAL DYSFUNCTION AND VASOOCCLUSION IN SICKLE CELL ANEMIA
-
批准号:6272917
-
项目类别:
-
资助金额:$23.22万
-
财政年份:1998
-
负责人:VIJAY K. KALRA
-
依托单位:
CORE--ADHESION CORE LABORATORY
-
批准号:6242182
-
项目类别:
-
资助金额:$16.57万
-
财政年份:1997
-
负责人:VIJAY K. KALRA
-
依托单位:
MECHANISMS OF RBC ADHESION AND ENDOTHELIAL INJURY IN SICKLE CELL DISEASE
-
批准号:6242176
-
项目类别:
-
资助金额:$16.57万
-
财政年份:1997
-
负责人:VIJAY K. KALRA
-
依托单位:
CORE--ADHESION CORE LABORATORY
-
批准号:5213968
-
项目类别:
-
资助金额:$0.0万
-
财政年份:--
-
负责人:VIJAY K. KALRA
-
依托单位:--
ROLE OF ENDOTHELIN-1 INSICKLEACUTE CHEST SYNDROME
-
批准号:7246527
-
项目类别:
-
资助金额:$35.95万
-
财政年份:--
-
负责人:VIJAY K. KALRA
-
依托单位:
ROLE OF ENDOTHELIN-1 INSICKLEACUTE CHEST SYNDROME
-
批准号:7446748
-
项目类别:
-
资助金额:$41.58万
-
财政年份:--
-
负责人:VIJAY K. KALRA
-
依托单位:
ROLE OF ENDOTHELIN-1 INSICKLEACUTE CHEST SYNDROME
-
批准号:7066627
-
项目类别:
-
资助金额:$34.91万
-
财政年份:--
-
负责人:VIJAY K. KALRA
-
依托单位:
MECHANISMS OF RBC ADHESION AND ENDOTHELIAL INJURY IN SICKLE CELL DISEASE
-
批准号:5213962
-
项目类别:
-
资助金额:$0.0万
-
财政年份:--
-
负责人:VIJAY K. KALRA
-
依托单位:--
海外基金