Cav-1.TRPV4 regulation of endothelial function in small pulmonary arteries
Cav-1.TRPV4对小肺动脉内皮功能的调节
基本信息
- 批准号:10394403
- 负责人:
- 金额:$ 49.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-15 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:Adenosine TriphosphateAgonistBindingCaveolaeChronicComplexDataDevelopmentDiagnosisDiseaseEndothelial CellsEndotheliumEventExposure toFoundationsFunctional disorderHumanHypoxiaImpairmentIndividualIntervention StudiesKnock-outKnockout MiceLungMediatingMusMyelin P2 ProteinNOS3 geneNitric OxidePathologicPatientsPeroxonitriteProgressive DiseaseProtein Kinase CPulmonary CirculationPulmonary HypertensionPulmonary artery structurePurinergic P2 ReceptorsPurinoceptorReactive Nitrogen SpeciesReceptor ActivationRegulationReportingRestScaffolding ProteinSignal PathwaySignal TransductionSignaling MoleculeSuperoxidesSystolic PressureTestingTherapeuticTherapeutic InterventionVanilloidVasodilationVasodilator AgentsVentricularbasecaveolin 1designdisease prognosisendothelial dysfunctionhuman subjectimprovedinsightmembermortalitymouse modelnew therapeutic targetnovelnovel therapeutic interventionpulmonary arterial hypertensionpulmonary arterial pressurereceptorshear stressvasoconstriction
项目摘要
Abstract
Pulmonary arterial hypertension (PAH) is a disease of pulmonary vasculature with a high mortality rate of up to
45% three years after diagnosis. PAH is often associated with the loss of endothelium-dependent vasodilation,
which has long been thought to be a major contributor to development of PAH. However, the underlying
mechanisms for the loss of endothelium-dependent vasodilation in PAH remain unclear, particularly in the native
endothelium from small pulmonary arteries (PAs) that control pulmonary arterial pressure. We recently showed
that endothelial TRPV4 (transient receptor potential vanilloid 4) channels are key regulators of endothelium-
dependent vasodilation in PAs. In this application, we provide novel preliminary data that endothelial TRPV4
channels regulate resting pulmonary arterial pressure (PAP), and are impaired in PAH. Moreover, we show that
scaffolding protein caveolin-1 provides a signaling platform for protein kinase C (PKC)-dependent regulation of
TRPV4 channels, a mechanism that is defective in PAH. Interestingly, two different peroxynitrite scavengers
restored endothelial TRPV4 channel activity in PAH, suggesting that peroxynitrite may be a key contributor to
dysfunction of TRPV4 channel function. Additionally, exogenous peroxynitrite also impaired caveolin-1·PKC
regulation of endothelial TRPV4 channel function. We, therefore, hypothesize that peroxynitrite-induced
impairment in caveolin-1·PKC regulation of TRPV4 channel function contributes to the loss of endothelium-
dependent vasodilation in PAH. In Specific Aim 1, we will use PAs from endothelium-specific TRPV4 and
caveolin-1 knockout mice and human lungs to define a novel caveolin-1·PKC·TRPV4 vasodilator signaling
complex that controls endothelial regulation of PAP. In Specific Aim 2, we will test the hypothesis that elevated
peroxynitrite levels disrupt caveolin-1·PKC·TRPV4 vasodilator signaling complex in PAH. We will also determine
whether lowering peroxynitrite levels in PAH reduces PAP in a TRPV4-dependent manner. These studies will
establish that abnormalities in endothelial TRPV4 channels in small PAs contribute to PAH, and lay the
foundation for novel therapeutic strategies to rescue endothelial TRPV4 channel function.
摘要
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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Swapnil K. Sonkusare其他文献
Sa1162: 3D ARCHITECTURE OF THE INTESTINAL MICROVASCULATURE AND ITS ASSOCIATION TO THE ENTERIC NERVOUS SYSTEM AND INNATE IMMUNE CELLS
- DOI:
10.1016/s0016-5085(22)60789-3 - 发表时间:
2022-05-01 - 期刊:
- 影响因子:
- 作者:
JeongMin Natalie Kim;Glynn B. Reno;Caitlin P. Hodges;Tatiana M. Midkiff;Christina B. Bagnati;Connor A. Schroeder;John N. Pignataro;Sean M. Ward;David G. Binion;Swapnil K. Sonkusare;Anthony J. Bauer - 通讯作者:
Anthony J. Bauer
Endothelial Pannexin 1–TRPV4 channel signaling lowers pulmonary arterial pressure
内皮 Pannexin 1–TRPV4 通道信号传导降低肺动脉压
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
Z. Daneva;Matteo Ottolini;Y. Chen;Eliška Klimentová;Soham A. Shah;R. Minshall;C. Seye;V. Laubach;B. Isakson;Swapnil K. Sonkusare - 通讯作者:
Swapnil K. Sonkusare
腸間膜血管内圧上昇に呼応した血管緊張におけるGDP/GTP交換因子p63RhoGEFの活性化
血管张力中 GDP/GTP 交换因子 p63RhoGEF 的激活响应肠系膜血管内压力增加
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Mykhaylo V. Artamonov;Swapnil K. Sonkusare;Miranda E. Good;Ko Momotani;Masumi Eto;Brant E. Isakson;Thu H. Le;Eric L. Cope;Zygmunt S. Derewenda;Urszula Derewenda;Avril V. Somlyo;坂井久美子 百渓江 - 通讯作者:
坂井久美子 百渓江
Expression of a β2 subunit mutant alters Ca currents in HL‐1 cells
β2 亚基突变体的表达改变 HL-1 细胞中的 Ca 电流
- DOI:
- 发表时间:
2006 - 期刊:
- 影响因子:0
- 作者:
Swapnil K. Sonkusare;J. Stimers;T. Grain;James DMarsh;S. Télémaque - 通讯作者:
S. Télémaque
Loss of local Ca2+ signaling networks in the endothelium in diet induced obesity
饮食引起的肥胖中内皮局部 Ca2 信号网络的丧失
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:0
- 作者:
Kwang;Eric L. Cope;Corina Marziano;Swapnil K. Sonkusare - 通讯作者:
Swapnil K. Sonkusare
Swapnil K. Sonkusare的其他文献
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{{ truncateString('Swapnil K. Sonkusare', 18)}}的其他基金
Novel Calcium Signaling Nanodomains in Vascular Smooth Muscle Cells
血管平滑肌细胞中的新型钙信号纳米结构域
- 批准号:
10744522 - 财政年份:2023
- 资助金额:
$ 49.75万 - 项目类别:
Impaired TRVP4-eNOS signaling in TM contributes to glaucoma
TM 中 TRVP4-eNOS 信号传导受损导致青光眼
- 批准号:
10503094 - 财政年份:2022
- 资助金额:
$ 49.75万 - 项目类别:
Impaired TRVP4-eNOS signaling in TM contributes to glaucoma
TM 中 TRVP4-eNOS 信号传导受损导致青光眼
- 批准号:
10880075 - 财政年份:2022
- 资助金额:
$ 49.75万 - 项目类别:
Cav-1.TRPV4 regulation of endothelial function in small pulmonary arteries
Cav-1.TRPV4对小肺动脉内皮功能的调节
- 批准号:
10163900 - 财政年份:2019
- 资助金额:
$ 49.75万 - 项目类别:
AKAP150-TRPV4 regulation of endothelial function in obesity
AKAP150-TRPV4 对肥胖内皮功能的调节
- 批准号:
10424433 - 财政年份:2019
- 资助金额:
$ 49.75万 - 项目类别:
Cav-1.TRPV4 regulation of endothelial function in small pulmonary arteries
Cav-1.TRPV4对小肺动脉内皮功能的调节
- 批准号:
9913574 - 财政年份:2019
- 资助金额:
$ 49.75万 - 项目类别:
AKAP150-TRPV4 regulation of endothelial function in obesity
AKAP150-TRPV4 对肥胖内皮功能的调节
- 批准号:
9925820 - 财政年份:2019
- 资助金额:
$ 49.75万 - 项目类别:
AKAP150-TRPV4 regulation of endothelial function in obesity
AKAP150-TRPV4 对肥胖内皮功能的调节
- 批准号:
10199007 - 财政年份:2019
- 资助金额:
$ 49.75万 - 项目类别:
AKAP150-TRPV4 regulation of endothelial function in obesity
AKAP150-TRPV4 对肥胖内皮功能的调节
- 批准号:
10630829 - 财政年份:2019
- 资助金额:
$ 49.75万 - 项目类别:
Cav-1.TRPV4 regulation of endothelial function in small pulmonary arteries
Cav-1.TRPV4对小肺动脉内皮功能的调节
- 批准号:
10621152 - 财政年份:2019
- 资助金额:
$ 49.75万 - 项目类别:
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