Metabolic regulation of Ca2+ entry and endothelial-mesenchymal transition in pulmonary arterial hypertension
肺动脉高压中 Ca2+ 进入和内皮-间质转化的代谢调节
基本信息
- 批准号:10295118
- 负责人:
- 金额:$ 40.3万
- 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
- 起止时间:2021-09-20 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:Anaerobic BacteriaBiological ModelsBiophysicsBlood VesselsCalciumCalcium ChannelCalcium SignalingCell physiologyCessation of lifeDataDevelopmentDiseaseDistalEndothelial CellsEndotheliumExhibitsFailureFatty AcidsFunctional disorderGenerationsGenesGlucoseGlycolysisHomeostasisHumanHypoxiaIn VitroInterruptionKnock-outLinkLungMesenchymalMetabolicMetabolic ActivationMetabolic dysfunctionMetabolismMethodsMicrovascular ProliferationMitochondriaMolecular TargetMusOxidative PhosphorylationPathogenicityPathway interactionsPatientsPhenotypePlayPre-Clinical ModelProductionPulmonary artery structureRattusReactive Oxygen SpeciesRegulationReporterReportingRespirationRodent ModelRoleSamplingSerumSignal TransductionSmooth MuscleSupplementationTestingTransgenic MiceTransgenic OrganismsVanilloidVascular remodelingVasodilationVentricularWorkbeta-Hydroxybutyrateendothelial dysfunctionexperimental studyfatty acid metabolismfatty acid oxidationin vivoinsightlive cell imagingmigrationmitochondrial dysfunctionmitochondrial metabolismnew therapeutic targetnovelnovel therapeuticsoverexpressionpressurepromoterpulmonary arterial hypertensionreceptortargeted treatment
项目摘要
PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is a lethal disease characterized by abnormal
proliferation of microvascular endothelial cells (MVECs) in the distal blood vessels of the lung. There are
currently no therapies that target the underlying endothelial dysfunction in PAH. Mitochondrial dysfunction,
increased intracellular calcium ([Ca2+]i) and endothelial-mesenchymal transition (EndMT) are important
pathogenic abnormalities observed in MVECs isolated from patients with PAH, but the mechanisms that link
these cellular abnormalities is unknown. In MVECs isolated from rats undergoing Sugen/Hypoxia (SuHx), an
experimental form of PAH (SuHx-MVECs), our prior work and current preliminary data suggest a)
mitochondrial dysfunction recapitulating those seen in human PAH ECs, b) increased mitochondrial reactive
oxygen species (mtROS) and β-hydroxybutyrate (BOHB), c) increased activation of the transient receptor
potential vanilloid-4 (TRPV4) channel and increased intracellular calcium ([Ca2+]i), d) EndMT and e) increased
proliferation. Further, we also observe specific shifts in metabolism (increased use of anaerobic respiration as
well as an increase in fatty acid oxidation), suggesting a metabolic basis for mitochondrial dysfunction in SuHx-
MVECs. Our preliminary data now suggest specific roles for two metabolic byproducts of increased fatty acid
oxidation – BOHB and mtROS - in sensitizing and activating TRPV4, respectively. Thus, we hypothesize that,
in PAH, a shift in MVEC mitochondrial metabolism from glycolysis to fatty acid oxidation promotes mtROS and
BOHB generation, leading to TRPV4 activation and consequently, Ca2+-dependent activation of EndMT and
proliferation. Using MVECs isolated from rats, mice and humans with and without PAH, as well as in vivo
experiments utilizing various novel transgenic rats and mice, we propose the three independent aims centered
around the following questions: 1) How does increased fatty acid oxidation promote TRPV4 activation in
MVECs; 2) Is TRPV4 activation necessary and sufficient to induce EndMT; and 3) What is the impact of
TRPV4 loss or BOHB supplementation on EndMT development in vivo. To accomplish these aims, we plan on
utilizing a variety of methods ranging from fluorescent live-cell imaging of MVECs isolated from WT and
transgenic mice and rats, in vitro studies in human MVECs from PAH patients (and controls), and in vivo
lineage-tracing studies to examine EndMT development in rodent models of PAH. Completion of these aims
will provide novel insight into the interplay between fatty acid metabolism, Ca2+ homeostasis and EndMT in
normal MVECs and role of the metabolic dysfunction and increased [Ca2+]I and EndMT in PAH.
项目摘要肺动脉高压(PAH)是一种以异常为特征的致命性疾病
肺远端血管内微血管内皮细胞(MVECs)增殖。确实有
目前还没有针对PAH潜在内皮功能障碍的治疗方法。线粒体功能障碍,
细胞内钙([Ca+]i)升高和内皮-间充质转化(EndMT)是重要的
从PAH患者分离的MVEC中观察到的致病异常,但其联系的机制
这些细胞异常是未知的。在SUGEN/低氧(SuHx)大鼠分离的MVECs中,
多环芳烃的实验形式(SuHx-MVECs),我们先前的工作和目前的初步数据表明:a)
线粒体功能障碍概括了人类PAH内皮细胞的功能障碍,b)增加了线粒体反应
氧物种(MtROS)和β-羟基丁酸酯(BOHb),c)增加瞬时受体的激活
潜在的香草酸-4(TRPV4)通道和细胞内钙([Ca~(2+)]i,d)EndMT和e)增加
扩散。此外,我们还观察到新陈代谢的特定变化(增加无氧呼吸的使用
以及脂肪酸氧化增加),提示SuHx-线粒体功能障碍的代谢基础-
MVEC。我们的初步数据现在表明,脂肪酸增加的两种代谢副产物具有特定的作用
氧化-BOHB和mtROS-in分别敏化和激活TRPV4。因此,我们假设,
在PAH中,MVEC线粒体代谢从糖酵解转变为脂肪酸氧化促进mtROS和
BOHB的产生,导致TRPV4激活,从而导致EndMT和EndMT的钙依赖激活
扩散。使用从有无PAH的大鼠、小鼠和人体内分离的MVECs,以及在体内
利用各种新型转基因大鼠和小鼠的实验,我们提出了三个独立的目标
围绕以下问题:1)增加的脂肪酸氧化如何促进TRPV4的激活
微血管内皮细胞;2)TRPV4的激活是诱导EndMT的必要条件和充分条件;以及3)
TRPV4缺失或补充BOHB对体内EndMT发育的影响。为了实现这些目标,我们计划
利用多种方法,从WT和WT分离的MVECs进行荧光活细胞成像
转基因小鼠和大鼠,来自PAH患者(和对照组)的人MVECs的体外研究和体内研究
家系追踪研究在PAH啮齿动物模型中的EndMT发育。完成这些目标
将为脂肪酸代谢、钙稳态和EndMT之间的相互作用提供新的见解。
正常微血管内皮细胞及代谢紊乱在PAH中的作用及升高的[Ca~(2+)]i和EndMT。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Karthik Suresh其他文献
Karthik Suresh的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Karthik Suresh', 18)}}的其他基金
Metabolic regulation of Ca2+ entry and endothelial-mesenchymal transition in pulmonary arterial hypertension
肺动脉高压中 Ca2+ 进入和内皮-间质转化的代谢调节
- 批准号:
10491235 - 财政年份:2021
- 资助金额:
$ 40.3万 - 项目类别:
Metabolic regulation of Ca2+ entry and endothelial-mesenchymal transition in pulmonary arterial hypertension
肺动脉高压中 Ca2+ 进入和内皮-间质转化的代谢调节
- 批准号:
10683247 - 财政年份:2021
- 资助金额:
$ 40.3万 - 项目类别:
ROS-induced endothelial dysfunction in pulmonary arterial hypertension
ROS诱导的肺动脉高压内皮功能障碍
- 批准号:
10205146 - 财政年份:2017
- 资助金额:
$ 40.3万 - 项目类别:
ROS-induced endothelial dysfunction in pulmonary arterial hypertension
ROS诱导的肺动脉高压内皮功能障碍
- 批准号:
9385047 - 财政年份:2017
- 资助金额:
$ 40.3万 - 项目类别:
Role of CD36 in ROS induced Ca influx in lung microvascular endothelial cells
CD36 在 ROS 诱导肺微血管内皮细胞 Ca 离子内流中的作用
- 批准号:
8784310 - 财政年份:2014
- 资助金额:
$ 40.3万 - 项目类别:
Role of CD36 in ROS induced Ca influx in lung microvascular endothelial cells
CD36 在 ROS 诱导肺微血管内皮细胞 Ca 离子内流中的作用
- 批准号:
8968762 - 财政年份:2014
- 资助金额:
$ 40.3万 - 项目类别:
相似海外基金
Nonlocal Variational Problems from Physical and Biological Models
物理和生物模型的非局部变分问题
- 批准号:
2306962 - 财政年份:2023
- 资助金额:
$ 40.3万 - 项目类别:
Standard Grant
Point-of-care optical spectroscopy platform and novel ratio-metric algorithms for rapid and systematic functional characterization of biological models in vivo
即时光学光谱平台和新颖的比率度量算法,可快速、系统地表征体内生物模型的功能
- 批准号:
10655174 - 财政年份:2023
- 资助金额:
$ 40.3万 - 项目类别:
Multi-scale stochastic systems motivated by biological models
由生物模型驱动的多尺度随机系统
- 批准号:
RGPIN-2015-06573 - 财政年份:2022
- 资助金额:
$ 40.3万 - 项目类别:
Discovery Grants Program - Individual
Micro-electrofluidic platforms for monitoring 3D human biological models
用于监测 3D 人体生物模型的微电流体平台
- 批准号:
DP220102872 - 财政年份:2022
- 资助金额:
$ 40.3万 - 项目类别:
Discovery Projects
Multi-scale stochastic systems motivated by biological models
由生物模型驱动的多尺度随机系统
- 批准号:
RGPIN-2015-06573 - 财政年份:2021
- 资助金额:
$ 40.3万 - 项目类别:
Discovery Grants Program - Individual
Multi-scale stochastic systems motivated by biological models
由生物模型驱动的多尺度随机系统
- 批准号:
RGPIN-2015-06573 - 财政年份:2020
- 资助金额:
$ 40.3万 - 项目类别:
Discovery Grants Program - Individual
Harnessing machine learning and cloud computing to test biological models of the role of white matter in human learning
利用机器学习和云计算来测试白质在人类学习中的作用的生物模型
- 批准号:
2004877 - 财政年份:2020
- 资助金额:
$ 40.3万 - 项目类别:
Fellowship Award
A Portable low-cost, Point of Investigation CapCell Scope to Image and Quantify the Major Axes of Metabolism and the Associated Vasculature in In vitro and In vivo Biological Models
便携式低成本调查点 CapCell 示波器,用于对体外和体内生物模型中的主要代谢轴和相关脉管系统进行成像和量化
- 批准号:
9899988 - 财政年份:2019
- 资助金额:
$ 40.3万 - 项目类别:
Multi-scale stochastic systems motivated by biological models
由生物模型驱动的多尺度随机系统
- 批准号:
RGPIN-2015-06573 - 财政年份:2019
- 资助金额:
$ 40.3万 - 项目类别:
Discovery Grants Program - Individual
A Portable low-cost, Point of Investigation CapCell Scope to Image and Quantify the Major Axes of Metabolism and the Associated Vasculature in In vitro and In vivo Biological Models
便携式低成本调查点 CapCell 示波器,用于对体外和体内生物模型中的主要代谢轴和相关脉管系统进行成像和量化
- 批准号:
9753458 - 财政年份:2019
- 资助金额:
$ 40.3万 - 项目类别: