Role of Endothelial Anoctamin-1 in Pulmonary Arterial Hypertension
内皮 Anoctamin-1 在肺动脉高压中的作用
基本信息
- 批准号:9803089
- 负责人:
- 金额:$ 43.08万
- 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:2019-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsApoptosisApoptoticAttenuatedBlood VesselsCalciumCell LineCell ProliferationCell Proliferation RegulationCell membraneCellsChloride ChannelsChloridesConflict (Psychology)DNADNA MethylationDiseaseDissociationEndothelial CellsEndotheliumEpidermal Growth Factor ReceptorEpigenetic ProcessFoundationsGrowthIn VitroInhalationIon ChannelLesionLungMalignant NeoplasmsMedialMediatingMethylationMitochondriaMorbidity - disease rateOPA1 geneOptic AtrophyOutcomePathologyPatientsPharmacologyPhenotypePre-Clinical ModelProteinsPulmonary HypertensionPulmonary artery structureRattusRegulatory ElementResistanceRoleSignal PathwaySignal TransductionSiteTestingTherapeuticTissuesVascular remodelingdesigneffective therapyimprovedin vitro testingin vivomethylation patternmortalitynovelnovel therapeuticsoverexpressionpreclinical studypressurepreventpulmonary arterial hypertensionresponsesmall moleculetreatment strategyvasoconstriction
项目摘要
ABSTRACT
Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. PAH pathology
includes vasoconstriction, medial and adventitial remodeling, and microvascular endothelial cell (EC)
proliferation leading to vaso-occlusive plexiform lesions. EC in PAH are both apoptosis resistant and
hyperproliferative. There are no effective treatments for the severe vascular remodeling observed with PAH,
and therapeutic strategies that target the dysfunctional EC and plexiform lesions are urgently needed. We
have discovered that calcium activated chloride channel, Ano1, is localized to both the EC plasma membrane
(pl-Ano1) and mitochondria (mito-Ano1). Ano1 expression is upregulated in EC in settings of PAH and
associated with a hyperproliferative and apoptosis resistant phenotype. However, unregulated activation of this
channel results in apoptosis of hyperproliferative apoptosis-resistant ECs. Our overall objective in this
proposal is to delineate the mechanisms underlying these seemingly conflicting observations to identify
therapeutic opportunities to decrease EC proliferation and target hyperproliferative ECs for apoptosis, thereby
improving pulmonary vascular remodeling in PAH. We hypothesize that epigenetically regulated increased
expression of Ano1 results in EC proliferation and apoptosis resistance, yet unregulated opening of Ano1 in the
context of overexpression is detrimental and can potentially be exploited to promote apoptosis of
hyperproliferative ECs in PAH. In Aim 1, we will determine the mechanism of increased Ano1 expression in
PAH EC with a focus on DNA methylation. We will use complementary in vitro and in vivo approaches to
design novel constructs to selectively alter the methylation pattern of Ano1 regulatory elements in lung EC and
test if this strategy prevents or treats PAH. In Aim 2, we will determine the effect of increased pl- and mito-
Ano1 expression on EC proliferation and apoptosis resistance and elucidate the underlying mechanisms. We
will investigate the signaling pathways in vitro and then use selective inhibition of Ano1 expression in lung EC
in vivo to determine its effect on preventing or treating PAH. In Aim 3, we will determine the mechanism of the
effect of pl- and mito-Ano-1 opening on EC apoptosis in vitro and test if opening of Ano1 by a small molecule
delivered by inhalation attenuates PAH. As a result of these studies we expect to delineate the mechanism of
Ano1-mediated EC proliferation and apoptosis resistance in settings of PAH as well as develop novel
therapeutic strategy targeting Ano1 to improve pulmonary vascular remodeling and PAH.
摘要
肺动脉高压(PAH)与显著的发病率和死亡率相关。PAH病理学
包括血管收缩、中膜和外膜重塑以及微血管内皮细胞(EC)
增殖导致血管闭塞性丛状病变。PAH中的EC既抗凋亡,
过度增殖对于PAH中观察到的重度血管重塑,尚无有效的治疗方法,
因此迫切需要针对功能失调的EC和丛状病变的治疗策略。我们
我发现钙激活的氯离子通道Ano 1定位于EC质膜,
(pl-Ano 1)和线粒体(mito-Ano 1)。在PAH的情况下,EC中Ano 1表达上调,
与过度增殖和抗凋亡表型相关。然而,这种不受调节的激活
通道导致过度增殖的抗凋亡EC的凋亡。我们在这方面的总体目标
建议是描述这些看似矛盾的观察背后的机制,以确定
减少EC增殖和靶向过度增殖的EC进行凋亡的治疗机会,从而
改善PAH中的肺血管重塑。我们假设表观遗传调节增加了
Ano 1的表达导致EC增殖和凋亡抵抗,但Ano 1在EC中的不受调节的开放,
过度表达的背景是有害的,并且可以潜在地被利用来促进细胞凋亡。
PAH中过度增殖的EC。在目标1中,我们将确定在细胞中增加Ano 1表达的机制。
PAH EC关注DNA甲基化。我们将使用互补的体外和体内方法,
设计新的构建体以选择性地改变肺EC中Ano 1调节元件的甲基化模式,
测试这种策略是否可以预防或治疗PAH。在目标2中,我们将确定增加pl-和mito-的影响。
Ano 1表达对EC增殖和凋亡抵抗的影响并阐明其机制。我们
将研究体外信号通路,然后使用选择性抑制肺EC中的Ano 1表达
以确定其对预防或治疗PAH的作用。在目标3中,我们将确定
pI-和mito-Ano-1开放对体外EC凋亡影响以及小分子是否开放Ano 1的测试
通过吸入递送的药物减弱PAH。作为这些研究的结果,我们期望描绘出
Ano 1介导的PAH环境中EC增殖和凋亡抵抗以及开发新的
靶向Ano 1的治疗策略,以改善肺血管重塑和PAH。
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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Gaurav Choudhary其他文献
Gaurav Choudhary的其他文献
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{{ truncateString('Gaurav Choudhary', 18)}}的其他基金
Deep learning for algorithmic detection of pulmonary hypertension using a combined digital stethoscope and single-lead electrocardiogram
使用组合数字听诊器和单导联心电图进行肺动脉高压算法检测的深度学习
- 批准号:
10705310 - 财政年份:2022
- 资助金额:
$ 43.08万 - 项目类别:
Deep learning for algorithmic detection of pulmonary hypertension using a combined digital stethoscope and single-lead electrocardiogram
使用组合数字听诊器和单导联心电图进行肺动脉高压算法检测的深度学习
- 批准号:
10547726 - 财政年份:2022
- 资助金额:
$ 43.08万 - 项目类别:
Role of Skeletal Muscle Mitochondrial Supercomplexes in Exercise Intolerance
骨骼肌线粒体超级复合物在运动不耐受中的作用
- 批准号:
10292886 - 财政年份:2019
- 资助金额:
$ 43.08万 - 项目类别:
Role of Endothelial Anoctamin-1 in Pulmonary Arterial Hypertension
内皮 Anoctamin-1 在肺动脉高压中的作用
- 批准号:
10200883 - 财政年份:2019
- 资助金额:
$ 43.08万 - 项目类别:
Role of Endothelial Anoctamin-1 in Pulmonary Arterial Hypertension
内皮 Anoctamin-1 在肺动脉高压中的作用
- 批准号:
10449284 - 财政年份:2019
- 资助金额:
$ 43.08万 - 项目类别:
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