Role of TRPV4 channel signaling in lung ischemia-reperfusion injury
Role of TRPV4 channel signaling in lung ischemia-reperfusion injury
批准号:
10181419
负责人:
Victor E Laubach
金额:
$65.78万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-04-15 至 2025-03-31
关键词:
AcuteAcute Lung InjuryAffectAgonistAlveolarAnimalsArteriesAttenuatedBone MarrowBronchiolitis ObliteransCalciumCalcium ChannelCationsCellsChronicClinical TrialsCoupledCouplingDataEdemaEndothelial CellsEndotheliumEpithelialEpithelial CellsExposure toFamily suidaeFunctional disorderGraft RejectionHeart failureHypoxiaImmuneIn VitroInfiltrationInflammationInflammation MediatorsInflammatoryKnockout MiceLeftLeukocytesLungLung TransplantationMediatingMediator of activation proteinMolecularMorbidity - disease rateMusNADPH OxidaseOxidative StressP2Y2 receptorPatientsPatternPermeabilityPharmacologyPhosphorylationPreventionPreventive therapyProteinsPulmonary EdemaPulmonary artery structureReactive Oxygen SpeciesReceptor SignalingReperfusion InjuryReportingRisk FactorsRoleSignal TransductionSourceSumTestingTherapeuticTranslatingTransplant RecipientsTransplantationVanilloidVascular Endothelial CellVascular PermeabilitiesWild Type Mousealveolar epitheliumcell typeclinically relevantdriving forceextracellularimprovedin vivoinflammatory lung diseaseinhibitor/antagonistinsightlung allograftlung ischemiamacrophagemonolayermortalityneutrophilnew therapeutic targetnovelpreventprophylacticpulmonary functionreceptorsuccesstherapeutic targettherapeutically effectivetransplant modeluptakevascular inflammation
中文摘要
项目摘要
原发移植物功能障碍发生率高,限制了肺移植的成功。
缺血再灌注损伤(IRI)的特点是强烈的炎症反应,血管通透性,
和肺泡损伤。IRI也是移植物晚期排斥反应(闭塞性细支气管炎)的危险因素。
移植后一年以上死亡的主要原因。TRPV4是一种跨膜钙
通道在多种细胞类型中表达,包括血管内皮细胞、肺泡细胞
上皮细胞、巨噬细胞和中性粒细胞。TRPV4激活可诱发肺损伤
内皮/上皮屏障功能障碍,这是IRI的关键特征,我们的数据表明
内皮细胞内TRPV4活性是肺缺血再灌注损伤的重要介质,其抑制作用
TRPV4活性的一部分具有显著的保护作用。我们还表明,TRPV4的活性可能会受到影响
由内皮细胞上的pAnnexin(Panx1)通道释放的ATP。因此,我们的提案将考验整体
内皮细胞TRPV4通道信号是肺IRI的关键介质的假说
导致内皮屏障破坏、血管通透性和白细胞浸润。目标1将
确定内皮细胞上的TRPV4活性是否介导肺IRI导致内皮/上皮屏障
功能障碍、血管炎症和白细胞渗出。TRPV4在人类基因组中的潜在作用
肺泡上皮细胞、巨噬细胞和中性粒细胞也将在肺IRI期间进行评估。
AIM 2将通过测试确定内皮细胞中Panx1/TRPV4轴介导肺IRI的机制
认为TRPV4是由IR后Panx1通道释放的ATP激活的假说。我们会
还要确定TRPV4活性是否由NADPH氧化酶衍生的活性氧诱导
在IR之后。目标3将利用小鼠原位肺移植模型来破译
TRPV4在供受者细胞和移植后内皮细胞中的表达。此外,a
临床上,大型动物猪肺移植模型将被用来确定
药物抑制Panx1可预防移植后肺IRI。目前有
没有针对IRI的预防性治疗方法,我们的研究将为我们提供新的洞察机制。
并将TRPV4通道定义为预防IRI的新治疗靶点
肺移植后。
英文摘要
Project Summary
The success of lung transplantation is limited by high rates of primary graft dysfunction due to
ischemia-reperfusion injury (IRI) characterized by robust inflammation, vascular permeability,
and alveolar damage. IRI is also a risk factor for late graft rejection (bronchiolitis obliterans), the
major cause of mortality beyond one year of transplant. TRPV4 is a transmembrane calcium
channel expressed in numerous cell types including vascular endothelial cells (ECs), alveolar
epithelial cells, macrophages, and neutrophils. TRPV4 activation can induce lung
endothelial/epithelial barrier dysfunction, a critical feature of IRI, and our data suggests that
TRPV4 activity in endothelial cells (ECs) is a significant mediator of lung IRI and that inhibition
of TRPV4 activity is significantly protective. We also show that TRPV4 activity may be affected
by ATP released by pannexin (Panx1) channels on ECs. Thus, our proposal will test the overall
hypothesis that endothelial TRPV4 channel signaling is a critical mediator of lung IRI by
inducing endothelial barrier disruption, vascular permeability and leukocyte infiltration. Aim 1 will
determine if TRPV4 activity on ECs mediates lung IRI leading to endothelial/epithelial barrier
dysfunction, vascular inflammation, and leukocyte infiltration. A potential role for TRPV4 in
alveolar epithelial cells, macrophages, and neutrophils will also be evaluated during lung IRI.
Aim 2 will define mechanisms for a Panx1/TRPV4 axis in ECs that mediates lung IRI by testing
the hypothesis that TRPV4 is activated by ATP released by Panx1 channels after IR. We will
also determine if TRPV4 activity is induced by NADPH oxidase-derived reactive oxygen species
after IR. Aim 3 will utilize a murine orthotopic lung transplant model to decipher the role of
TRPV4 in donor versus recipient cells as well as in ECs after transplantation. In addition, a
clinically relevant, large animal porcine lung transplant model will be used to determine if
pharmacologic inhibition of Panx1 will prevent lung IRI after transplantation. There currently are
no preventative therapies for IRI, and our studies will provide novel insight into mechanisms of
lung IRI and will define TRPV4 channels as a novel therapeutic target for the prevention of IRI
after lung transplantation.
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会议论文
Role of TRPV4 channel signaling in lung ischemia-reperfusion injury
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批准号:10586084
-
项目类别:
-
资助金额:$70.49万
-
财政年份:2021
-
负责人:Victor E Laubach
-
依托单位:
Role of TRPV4 channel signaling in lung ischemia-reperfusion injury
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批准号:10391559
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项目类别:
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资助金额:$66.23万
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财政年份:2021
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负责人:Victor E Laubach
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依托单位:
Pannexin-1 Signaling in Lung Ischemia-Reperfusion Injury
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批准号:9898429
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项目类别:
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资助金额:$55.85万
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财政年份:2017
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负责人:Victor E Laubach
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依托单位:
Resident Leukocytes in Lung Ischemia-Reperfusion Injury
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批准号:7057840
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项目类别:
-
资助金额:$37.23万
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财政年份:2005
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负责人:Victor E Laubach
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依托单位:
Resident Leukocytes in Lung Ischemia-Reperfusion Injury
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批准号:6919071
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项目类别:
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资助金额:$37.34万
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财政年份:2005
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负责人:Victor E Laubach
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依托单位:
T cell-mediated lung ischemia-reperfusion injury
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批准号:8490408
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项目类别:
-
资助金额:$36.29万
-
财政年份:2005
-
负责人:Victor E Laubach
-
依托单位:
T cell-mediated lung ischemia-reperfusion injury
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批准号:7985780
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项目类别:
-
资助金额:$37.53万
-
财政年份:2005
-
负责人:Victor E Laubach
-
依托单位:
Resident Leukocytes in Lung Ischemia-Reperfusion Injury
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批准号:7409219
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项目类别:
-
资助金额:$36.15万
-
财政年份:2005
-
负责人:Victor E Laubach
-
依托单位:
T cell-mediated lung ischemia-reperfusion injury
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批准号:8267659
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项目类别:
-
资助金额:$38.12万
-
财政年份:2005
-
负责人:Victor E Laubach
-
依托单位:
Resident Leukocytes in Lung Ischemia-Reperfusion Injury
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批准号:7227088
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项目类别:
-
资助金额:$36.15万
-
财政年份:2005
-
负责人:Victor E Laubach
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依托单位:
Nitric Oxide Regulation of Compensatory Lung Growth
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批准号:6731184
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项目类别:
-
资助金额:$29.6万
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财政年份:2002
-
负责人:Victor E Laubach
-
依托单位:
Nitric Oxide Regulation of Compensatory Lung Growth
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批准号:6878468
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项目类别:
-
资助金额:$29.6万
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财政年份:2002
-
负责人:Victor E Laubach
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依托单位:
Nitric Oxide Regulation of Compensatory Lung Growth
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批准号:6471675
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项目类别:
-
资助金额:$28.52万
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财政年份:2002
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负责人:Victor E Laubach
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依托单位:
Nitric Oxide Regulation of Compensatory Lung Growth
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批准号:6623991
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项目类别:
-
资助金额:$29.6万
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财政年份:2002
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负责人:Victor E Laubach
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依托单位:
Cardiovascular Surgery Training Program
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批准号:9503752
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项目类别:
-
资助金额:$42.56万
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财政年份:1998
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负责人:Victor E Laubach
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依托单位:
海外基金