Molecular mechanisms of downregulated Kv channels in IPAH: Role of microRNA
IPAH 中 Kv 通道下调的分子机制:microRNA 的作用
基本信息
- 批准号:8895028
- 负责人:
- 金额:$ 45.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2017-05-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAffectApoptosisApoptoticBlood PressureBlood VesselsCaspaseCell ProliferationCell physiologyCellsCytoplasmDataDiseaseDown-RegulationGenetic TranslationGoalsHypertensionHypertrophyIn SituLeadLungMedialMediatingMembraneMessenger RNAMicroRNAsMolecularPatientsPotassium ChannelProgressive DiseasePulmonary Vascular ResistancePulmonary artery structureRNA BindingRegulationRoleSmooth Muscle MyocytesStimulusTestingTherapeuticThrombosisTranslationsVascular remodelingWomanabstractingbasedesignmRNA Transcript Degradationnew therapeutic targetnucleaseoverexpressionpulmonary arterial hypertensionvasoconstrictionvoltageyoung woman
项目摘要
Project Summary/Abstract
Idiopathic pulmonary arterial hypertension (IPAH) is a fatal and progressive disease that
predominantly affects women. Pulmonary vascular remodeling, sustained vasoconstriction and
in situ thrombosis are the major causes for the elevated pulmonary vascular resistance in IPAH
patients. Pulmonary vascular remodeling is characterized in part by significant medial and
intimal hypertrophy, due to increased pulmonary arterial smooth muscle cell (PASMC)
proliferation and decreased PASMC apoptosis. A rise in cytosolic Ca ([Ca ]cyt) in PASMC is a
2+ 2+
major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation.
Downregulation of voltage-gated K (Kv) channel expression and decrease in Kv currents (IK(V))
+
contribute to a) increasing PASMC proliferation by raising [Ca ]cyt via membrane depolarization
2+
and b) decreasing PASMC apoptosis by inhibiting apoptotic volume decrease and maintaining
sufficient K+ in the cytoplasm to inhibit caspases and nucleases. Our data showed that the
expression and activity of Kv channels are reduced, while proliferation is enhanced and
apoptosis is inhibited, in IPAH-PASMC compared to normal PASMC. MicroRNAs (miRNAs) are
short RNAs that bind to complementary sequences in the 3'-untranslated regions (3'-UTR) of
target mRNAs to inhibit mRNA translation and/or induce mRNA degradation, thereby inhibiting
the expression of specific mRNA targets. miRNAs are thus posttranscriptional regulators that
potentially regulate the level of Kv channel mRNAs in IPAH-PASMC. We recently identified
several miRNAs (e.g., miR-29b, miR-138 and miR-222) that are highly expressed, whereas
several Kv channels (e.g., KCNA1-7/10) are significantly downregulated, in IPAH-PASMC
compared to normal PASMC. Overexpression of miR-29b, miR-138 or miR-222 in normal
PASMC decreases whole-cell IK(V), whereas inhibition of miR-29b rescues (i.e., significantly
enhances) IK(V) in IPAH-PASMC. These data suggest that miR-138, miR-222 and miR-29b are
sufficient to decrease IK(V) in normal PASMC, while miR-29b is necessary for the decreased IK(V)
in IPAH-PASMC. Based on these observations, we hypothesize that selectively upregulated
miRNAs are involved in the posttranscriptional inhibition of Kv channels in IPAH-PASMC and the
miRNA-mediated Kv channel inhibition contributes to increasing proliferation and decreasing
apoptosis in IPAH-PASMC. Three Specific Aims are proposed to test this hypothesis: 1) To
identify the miRNAs that are upregulated and the Kv channels that are downregulated in IPAH-
PASMC, and to determine which Kv channel subunits are posttranscriptionally regulated by the
upregulated miRNAs in IPAH-PASMC; 2) To determine whether upregulated miRNAs in IPAH-
PASMC regulate the stability and translation of target Kv channel mRNAs; and 3) To determine
the role of miRNA-mediated posttranscriptional inhibition of Kv channels in PASMC proliferation
and apoptosis. The long-term goal of this study is to define the mechanism underlying the
inhibition of Kv channels in IPAHPASMC and to explore the possibility to target miRNA for
developing therapeutic approaches for IPAH.
项目总结/摘要
特发性肺动脉高压(IPAH)是一种致命的进行性疾病,
主要影响女性。肺血管重塑,持续的血管收缩和
原位血栓形成是IPAH肺血管阻力升高的主要原因
患者肺血管重构的特征部分在于显著的中膜和膜损伤。
内膜肥大,由于肺动脉平滑肌细胞(PASMC)增加
增殖和减少PASMC凋亡。PASMC中胞浆Ca([Ca ]cyt)的升高是一个重要因素。
2+ 2+
肺血管收缩的主要触发因素和PASMC增殖的重要刺激因素。
电压门控K(Kv)通道表达下调和Kv电流(IK(V))降低
+
有助于a)通过经由膜去极化提高[Ca ]cyt来增加PASMC增殖
2个以上
和B)通过抑制细胞凋亡体积减少和维持PASMC的细胞凋亡,
细胞质中足够的K+抑制半胱天冬酶和核酸酶。我们的数据显示,
Kv通道的表达和活性降低,而增殖增强,
与正常PASMC相比,IPAH-PASMC的细胞凋亡受到抑制。微小RNA(miRNAs)是
短RNA,其结合至细胞的3 '-非翻译区(3'-UTR)中的互补序列,
靶向mRNA以抑制mRNA翻译和/或诱导mRNA降解,从而抑制
特定mRNA靶点的表达。因此,miRNA是转录后调节因子,
可能调节IPAH-PASMC中Kv通道mRNA的水平。我们最近发现
几种miRNA(例如,miR-29 b、miR-138和miR-222),而
几个KV信道(例如,KCNA 1 -7/10)在IPAH-PASMC中显著下调,
与正常的PASMC相比。miR-29 b、miR-138或miR-222在正常人中的过表达
PASMC降低了全细胞IK(V),而miR-29 b的抑制挽救了(即,显著
增强)IK(V)。这些数据表明,miR-138、miR-222和miR-29 b是
足以降低正常PASMC中的IK(V),而miR-29 b是降低IK(V)所必需的
在IPAH-PASMC。基于这些观察,我们假设选择性上调
miRNAs参与IPAH-PASMC中Kv通道的转录后抑制,
miRNA介导的Kv通道抑制有助于增加增殖和减少细胞凋亡。
IPAH-PASMC凋亡。提出了三个具体目标来检验这一假设:1)
鉴定在IPAH中上调的miRNAs和下调的Kv通道。
PASMC,并确定哪些Kv通道亚基是由PASMC转录后调节的。
2)为了确定IPAH-PASMC中的上调的miRNAs是否在IPAH-PASMC中表达,
PASMC调节靶Kv通道mRNA的稳定性和翻译;以及3)为了确定
miRNA介导Kv通道转录后抑制在PASMC增殖中的作用
和凋亡。这项研究的长期目标是确定潜在的机制,
抑制IPAHPASMC中的Kv通道,并探索靶向miRNA的可能性,
开发IPAH的治疗方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jason X J Yuan的其他文献
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{{ truncateString('Jason X J Yuan', 18)}}的其他基金
Pre-Clinical Models of VILI /ARDS Core
VILI /ARDS Core 的临床前模型
- 批准号:
10094244 - 财政年份:2018
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$ 45.73万 - 项目类别:
Ion Channels and Membrane Receptors in Pulmonary Arterial Hypertension
肺动脉高压中的离子通道和膜受体
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10334539 - 财政年份:2017
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$ 45.73万 - 项目类别:
Ion Channels and Membrane Receptors in Pulmonary Arterial Hypertension
肺动脉高压中的离子通道和膜受体
- 批准号:
10163893 - 财政年份:2017
- 资助金额:
$ 45.73万 - 项目类别:
Ion Channels and Membrane Receptors in Pulmonary Arterial Hypertension
肺动脉高压中的离子通道和膜受体
- 批准号:
9927824 - 财政年份:2017
- 资助金额:
$ 45.73万 - 项目类别:
Ion Channels and Membrane Receptors in Pulmonary Arterial Hypertension
肺动脉高压中的离子通道和膜受体
- 批准号:
9457280 - 财政年份:2017
- 资助金额:
$ 45.73万 - 项目类别:
Ion Channels and Membrane Receptors in Pulmonary Arterial Hypertension
肺动脉高压中的离子通道和膜受体
- 批准号:
10563148 - 财政年份:2017
- 资助金额:
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Ion Channels and Membrane Receptors in Pulmonary Arterial Hypertension
肺动脉高压中的离子通道和膜受体
- 批准号:
10022708 - 财政年份:2017
- 资助金额:
$ 45.73万 - 项目类别:
Molecular mechanisms of downregulated Kv channels in IPAH: Role of microRNA
IPAH 中 Kv 通道下调的分子机制:microRNA 的作用
- 批准号:
8534280 - 财政年份:2012
- 资助金额:
$ 45.73万 - 项目类别:
Molecular mechanisms of downregulated Kv channels in IPAH: Role of microRNA
IPAH 中 Kv 通道下调的分子机制:microRNA 的作用
- 批准号:
9066768 - 财政年份:2012
- 资助金额:
$ 45.73万 - 项目类别:
Molecular mechanisms of downregulated Kv channels in IPAH: Role of microRNA
IPAH 中 Kv 通道下调的分子机制:microRNA 的作用
- 批准号:
8775024 - 财政年份:2012
- 资助金额:
$ 45.73万 - 项目类别:
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