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)与严重的发病率和死亡率有关。PAH病理学
包括血管收缩、中膜和外膜重构以及微血管内皮细胞(EC)
增殖导致血管闭塞的丛状病变。PAH中的EC既能抗凋亡,又能
过度增殖。目前还没有有效的治疗方法来治疗PAH所致的严重血管重构。
而针对功能障碍的EC和丛状病变的治疗策略是迫切需要的。我们
发现钙激活的氯离子通道Ano1定位于EC质膜
(p1-Ano1)和线粒体(mito-Ano1)。在PAH和EC的设置中,Ano1的表达上调
与过度增殖和抗凋亡表型相关。然而,这种不受监管的激活
通道可导致高增殖、抗凋亡的内皮细胞发生凋亡。我们在这方面的总体目标
提议是描述这些看似相互矛盾的观察背后的机制,以确定
治疗机会,以减少内皮细胞的增殖和靶向高增殖的内皮细胞的凋亡,从而
改善PAH的肺血管重塑。我们假设表观遗传调控增加了
Ano1的表达导致内皮细胞增殖和凋亡抵抗,但Ano1的开放不受调控
过度表达的背景是有害的,可能被利用来促进细胞凋亡
PAH中过度增殖的内皮细胞。在目标1中,我们将确定Ano1表达增加的机制。
PAH EC,重点是DNA甲基化。我们将使用体外和体内互补的方法来
设计新的构建物来选择性地改变肺内皮细胞和肺组织中Ano1调节元件的甲基化模式
测试这一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-的效果。
Ano1表达对EC增殖和凋亡抵抗的影响并阐明其机制。我们
将在体外研究信号通路,然后选择性地抑制肺内皮细胞中Ano1的表达
以确定其预防或治疗PAH的作用。在目标3中,我们将确定
Pl-和mito-ANO-1开放对体外内皮细胞凋亡的影响及小分子开放Ano1的实验研究
吸入给药可减轻PAH。作为这些研究的结果,我们预计将描绘出
Ano1介导的血管内皮细胞增殖和凋亡抵抗在PAH中的研究进展
以血管内皮生长因子1为靶点改善肺血管重构和肺高压的治疗策略。
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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