Vascular Smooth Muscle Function in Pulmonary Hypertension
肺动脉高压中的血管平滑肌功能
基本信息
- 批准号:9207481
- 负责人:
- 金额:$ 37.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-02-01 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:ASIC channelAcidsActinsAcuteAffectAgonistAnimalsBiological AssayBiotinylationBlood CirculationBlood VesselsCalciumCationsCause of DeathCell membraneCell surfaceCellsCenters for Disease Control and Prevention (U.S.)ChronicChronic lung diseaseCytoskeletal ProteinsDevelopmentElectrophysiology (science)EtiologyFamily memberFatal OutcomeGene ProteinsGoalsHeart failureHomeostasisHydrogen PeroxideHypertensionHypoxiaImageInvestigationIon ChannelKnowledgeLabelLaboratoriesLeadLungLung diseasesMeasurementMeasuresMediatingMembraneMolecular BiologyMusMuscle functionOxidantsOxidation-ReductionPermeabilityPhosphotransferasesPhysiologicalPhysiologyPlayPreventive measureProductionProteinsPulmonary CirculationPulmonary HypertensionPulmonary Vascular ResistancePulmonary artery structureRattusRegulationResearchReticulumRoleScaffolding ProteinSleep Apnea SyndromesSmooth MuscleSmooth Muscle MyocytesStrokeSurfaceTestingTissuesUnited StatesUp-RegulationVascular Smooth MuscleVascular remodelingVasoconstrictor AgentsWorkWorld Health Organizationarterial remodelingbasecell typeconstrictiondisorder preventioneffective therapyin vivoinhibitor/antagonistinnovationlung hypoxianovelnovel therapeutic interventionpolymerizationpressureprogramsprotein expressionpublic health relevancereceptorresponsetraffickingvasoconstrictionvoltage
项目摘要
DESCRIPTION (provided by applicant): Chronic hypoxia (CH) associated with obstructive pulmonary disease and sleep apnea often results in generalized pulmonary arterial constriction and vascular remodeling, subsequent pulmonary hypertension and right heart failure. Pulmonary arterial smooth muscle cell (PASMC) intracellular calcium ([Ca2+]i) plays a vital role in establishing pulmonary vascular resistance and it has become increasingly evident that increased Ca2+ influx contributes to both the vasoconstrictor and vascular remodeling responses in CH-induced pulmonary hypertension. Our laboratory has found a novel role for acid sensing ion channel 1 (ASIC1) in mediating store-operated Ca2+ entry (SOCE) in PASMC following CH. However, little is known about the mechanism(s) that govern ASIC1 trafficking, stability, and activation in PASMC. In addition, it is unclear how CH alters these mechanism(s) to increase functional ASIC1 at the plasma membrane. The overall objective of this application is to establish an important role for ASIC1 in the development of CH-induced pulmonary hypertension and potential mechanisms involved in this response. We will test the central hypothesis that ASIC1, through a novel mechanism of SOCE in PASMC, contributes to CH-induced increases in vascular reactivity and pulmonary hypertension with the following specific aims: 1) Determine the contribution of ASIC1 to CH-induced pulmonary hypertension. We will test the hypothesis that ASIC1 contributes to the active vasoconstrictor component of CH-induced pulmonary hypertension by assessing in vivo measurements of pulmonary arterial pressure, arterial remodeling, and vasoreactivity. 2) Identify the mechanism(s) responsible for ASIC1 membrane trafficking and how this is altered by CH. We will test the hypothesis that CH promotes PICK1 (protein interacting with C- kinase 1)-dependent ASIC1 trafficking to the membrane through increased RhoA-mediated actin polymerization by use of cell surface biotinylation assays, [Ca2+]i imaging, and live-cell confocal imaging of a fluorescently- labeled ASIC1 protein. 3) Examine the effect of cellular redox potential on ASIC1 activation. We hypothesize that decreased hydrogen peroxide (H2O2) following CH increases ASIC1 surface expression and channel activity. We will assess vasoreactivity and conduct [Ca2+]i imaging and electrophysiology studies to examine the role of reducing/oxidizing agents and H2O2 on ASIC1 channel activity and trafficking in PASMC. The proposed research is innovative through its focus on the previously undefined mechanisms of ASIC1 membrane trafficking, channel regulation and Ca2+ influx in the normal pulmonary circulation. In addition, our work is at the forefront of determining how hypoxia affects ASIC1 function in the hypertensive circulation. Successful completion of the proposed research will provide a mechanistic-based understanding of how ASIC1 contributes to CH- induced pulmonary hypertension and will significantly advance our knowledge of the cellular mechanisms responsible for altered PASMC Ca2+ homeostasis and vasoconstriction in the hypertensive pulmonary circulation. Ultimately, such knowledge has the potential to provide new directions in pulmonary hypertension therapy.
描述(由申请人提供):与阻塞性肺疾病和睡眠呼吸暂停相关的慢性缺氧(CH)通常会导致全身性肺动脉收缩和血管重塑,随后出现肺动脉高压和右心衰竭。肺动脉平滑肌细胞(PASMC)胞内钙离子([Ca ~(2+)]i)在肺血管阻力的形成中起着重要的作用。我们的实验室已经发现了一个新的作用,酸敏感离子通道1(ASIC 1)介导的钙库操作的Ca 2+内流(SOCE)在PASMC后CH。然而,很少有人知道(S)的机制,管理ASIC 1运输,稳定性和激活PASMC。此外,尚不清楚CH如何改变这些机制以增加质膜上的功能性ASIC 1。本申请的总体目标是确定ASIC 1在CH诱导的肺动脉高压的发展中的重要作用以及参与这种反应的潜在机制。我们将检验中心假设,即ASIC 1通过PASMC中SOCE的新机制,有助于CH诱导的血管反应性和肺动脉高压的增加,具体目的如下:1)确定ASIC 1对CH诱导的肺动脉高压的贡献。我们将通过评估肺动脉压、动脉重塑和血管反应性的体内测量来检验ASIC 1参与CH诱导的肺动脉高压的活性血管收缩成分的假设。2)鉴定负责ASIC 1膜运输的机制以及CH如何改变这一机制。我们将通过使用细胞表面生物素化测定、[Ca 2 +]i成像和荧光标记的ASIC 1蛋白的活细胞共聚焦成像来测试CH通过增加RhoA介导的肌动蛋白聚合促进PICK 1(与C-激酶1相互作用的蛋白质)依赖性ASIC 1向膜的运输的假设。3)检查细胞氧化还原电位对ASIC 1激活的影响。我们假设CH后过氧化氢(H2 O2)减少会增加ASIC 1表面表达和通道活性。我们将评估血管反应性并进行[Ca 2 +]i成像和电生理学研究,以检查还原/氧化剂和H2 O2对PASMC中ASIC 1通道活性和运输的作用。这项研究是创新性的,因为它专注于以前未定义的ASIC 1膜运输,通道调节和正常肺循环中Ca 2+内流的机制。此外,我们的工作处于确定缺氧如何影响高血压循环中ASIC 1功能的最前沿。成功完成拟议的研究将提供一个机制为基础的理解,如何ASIC 1有助于CH-诱导的肺动脉高压,并将显着推进我们的细胞机制的知识,负责改变PASMC Ca 2+稳态和血管收缩在高血压肺循环。最终,这些知识有可能为肺动脉高压治疗提供新的方向。
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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Nikki L Jernigan其他文献
Nikki L Jernigan的其他文献
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{{ truncateString('Nikki L Jernigan', 18)}}的其他基金
Vascular Smooth Muscle Function in Pulmonary Hypertension
肺动脉高压中的血管平滑肌功能
- 批准号:
10402413 - 财政年份:2013
- 资助金额:
$ 37.75万 - 项目类别:
Vascular Smooth Muscle Function in Pulmonary Hypertension
肺动脉高压中的血管平滑肌功能
- 批准号:
8996696 - 财政年份:2013
- 资助金额:
$ 37.75万 - 项目类别:
Vascular Smooth Muscle Function in Pulmonary Hypertension
肺动脉高压中的血管平滑肌功能
- 批准号:
9919612 - 财政年份:2013
- 资助金额:
$ 37.75万 - 项目类别:
Vascular Smooth Muscle Function in Pulmonary Hypertension
肺动脉高压中的血管平滑肌功能
- 批准号:
8606497 - 财政年份:2013
- 资助金额:
$ 37.75万 - 项目类别:
Vascular Smooth Muscle Function in Pulmonary Hypertension
肺动脉高压中的血管平滑肌功能
- 批准号:
8794459 - 财政年份:2013
- 资助金额:
$ 37.75万 - 项目类别:
Vascular Smooth Muscle Function in Pulmonary Hypertension
肺动脉高压中的血管平滑肌功能
- 批准号:
10166899 - 财政年份:2013
- 资助金额:
$ 37.75万 - 项目类别:
Vascular Smooth Muscle Function in Pulmonary Hypertension
肺动脉高压中的血管平滑肌功能
- 批准号:
8436797 - 财政年份:2013
- 资助金额:
$ 37.75万 - 项目类别:
Role of Acid-Sensing Ion Channels in Pulmonary Vascular Smooth Muscle Store-Opera
酸敏感离子通道在肺血管平滑肌库中的作用-Opera
- 批准号:
7882669 - 财政年份:2008
- 资助金额:
$ 37.75万 - 项目类别:
Role of Acid-Sensing Ion Channels in Pulmonary Vascular Smooth Muscle Store-Opera
酸敏感离子通道在肺血管平滑肌库中的作用-Opera
- 批准号:
8261119 - 财政年份:2008
- 资助金额:
$ 37.75万 - 项目类别:
Role of Acid-Sensing Ion Channels in Pulmonary Vascular Smooth Muscle Store-Opera
酸敏感离子通道在肺血管平滑肌库中的作用-Opera
- 批准号:
8067830 - 财政年份:2008
- 资助金额:
$ 37.75万 - 项目类别:
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