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
基本信息
- 批准号:8968762
- 负责人:
- 金额:$ 5.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-20 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Lung InjuryAdult Respiratory Distress SyndromeAlveolusBindingBinding SitesBloodCD36 geneCalciumCellsCellular StressCritical IllnessDataDevelopmentDiseaseDrug DesignEndothelial CellsEndotheliumExposure toFatty AcidsFellowshipFloodsFunctional disorderGeneticGoalsHydrogen PeroxideImageImmuneImmunoblottingIndividualInjuryIschemiaLeadLinkLipid BindingLiquid substanceLungMeasurementMeasuresMediatingModelingMorbidity - disease rateMusNational Research Service AwardsNeuronsOxidantsOxygenPathogenesisPathway interactionsPatientsPermeabilityPharmaceutical PreparationsPhysiciansPlayProteinsPulmonary EdemaReactive Oxygen SpeciesRegulationReperfusion TherapyRoleRuthenium RedScientistSignal TransductionSmall Interfering RNAStimulusTestingTyrosine PhosphorylationVanilloidbasecell injuryextracellularin vivoin vivo Modelinhibitor/antagonistinjuredintravital microscopykinase inhibitorknock-downlung injurymembermortalitynoveloxidized lipidpreventpublic health relevancepulmonary vascular permeabilityreceptorresearch and developmentresearch studyresponsescavenger receptorshear stressskillssrc-Family Kinases
项目摘要
DESCRIPTION (provided by applicant): The objectives of this NRSA individual fellowship are to 1) facilitate the development of research skills that will allow the candidate to become an effective physician-scientist and 2) investigate the mechanisms behind oxidant induced endothelial Ca2+ influx and lung permeability in Acute Respiratory Distress Syndrome (ARDS). ARDS is a common, sometimes fatal lung condition characterized by increased permeability of the lung endothelium, allowing for fluid to enter the alveoli, resulting in an inability to oxygenae the blood. Reactive oxygen species (ROS) are oxygen derived molecules known to be increased in many diseases including ARDS, and also known to cause cellular stress and injury. In addition to ROS, abnormally high intracellular Ca2+ levels have been shown to lead to increased endothelial permeability. However, the relationship between ROS and Ca2+ entry into the lung endothelium remains unclear. The candidate has preliminary data that shows that Ca2+ levels in lung endothelial cells rise after they have been exposed to ROS, and that this rise in Ca2+ is absent in cells that are lacking a protein called CD36. CD36 is a receptor that normally binds fatty acids. It has been shown by others to participate in calcium and ROS signaling in immune and neuronal cells, but its role in lung endothelial cells has not been examined. The focus of this project is to examine how CD36 influences Ca2+ influx in response to ROS in the lung endothelium. The long-term goal of this proposal is to identify novel mechanisms of regulation of Ca2+ entry into endothelial cells that can be targeted by drugs designed to help patients in ARDS as well as other diseases where the endothelium is abnormally permeable. In Specific Aim 1, using fluorescent Ca2+ imaging and siRNA on lung endothelial cells, the candidate will test whether TRPV4, a Ca2+ channel shown in the candidate's preliminary studies to be possibly involved in ROS-induced Ca2+ entry, is the channel that is responsible for Ca2+ influx. In Specific Aim 2, using immunoblots and Ca2+ imaging on both normal endothelial cells and endothelial cells with genetic deletion of CD36, the effect of ROS on CD36 and another protein associated with CD36 called Fyn will be assessed. The goal of this aim will be to determine the pathway by which ROS eventually causes opening of Ca2+ channels. In Specific Aim 3, using a model of in vivo lung injury and measurement of in vivo Ca2+ in mice, the effect of drugs blocking various members of the proposed pathway linking ROS, CD36 and TRPV4 on calcium entry and development of lung edema will be tested. The goal of these experiments is to understand the mechanisms behind Ca2+ entry and subsequent loss of barrier function in lung endothelial cells injured by ROS.
描述(由申请人提供):该NRSA个人奖学金的目的是1)促进研究技能的发展,使候选人成为一名有效的医生-科学家,2)研究氧化剂诱导的内皮Ca 2+内流和急性呼吸窘迫综合征(ARDS)中肺渗透性的机制。ARDS是一种常见的,有时是致命的肺部疾病,其特征是肺内皮细胞的渗透性增加,允许液体进入肺泡,导致血液无法供氧。活性氧(ROS)是已知在包括ARDS的许多疾病中增加的氧衍生分子,并且还已知引起细胞应激和损伤。除了ROS,异常高的细胞内Ca 2+水平已被证明会导致内皮通透性增加。然而,ROS和Ca 2+进入肺内皮之间的关系仍不清楚。候选人的初步数据显示,肺内皮细胞中的Ca 2+水平在暴露于ROS后升高,并且这种Ca 2+的升高在缺乏称为CD 36的蛋白质的细胞中不存在。CD 36是一种通常与脂肪酸结合的受体。其他人已经表明它参与免疫和神经细胞中的钙和ROS信号传导,但其在肺内皮细胞中的作用尚未被研究。本项目的重点是研究CD 36如何影响肺内皮细胞对ROS反应的Ca 2+内流。该提案的长期目标是确定调节Ca 2+进入内皮细胞的新机制,这些机制可以被设计用于帮助ARDS患者以及内皮异常渗透的其他疾病的药物靶向。在特定目标1中,使用荧光Ca 2+成像和肺内皮细胞上的siRNA,候选人将测试TRPV 4(候选人初步研究中显示可能参与ROS诱导的Ca 2+内流的Ca 2+通道)是否是负责Ca 2+内流的通道。在特异性目的2中,将使用免疫印迹和Ca 2+成像对正常内皮细胞和CD 36基因缺失的内皮细胞进行评估,以评估ROS对CD 36和另一种与CD 36相关的蛋白质(称为Fyn)的影响。这一目标的目标是确定ROS最终导致Ca 2+通道开放的途径。在具体目标3中,使用体内肺损伤模型和小鼠体内Ca 2+测量,将测试阻断所提出的连接ROS、CD 36和TRPV 4的途径的各种成员的药物对钙进入和肺水肿发展的影响。这些实验的目的是了解ROS损伤的肺内皮细胞中Ca 2+进入和随后屏障功能丧失背后的机制。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Occupational Asthma Due to Inhalation of Aerosolized Lipophilic Coating Materials.
由于吸入雾化亲脂性涂层材料而引起的职业性哮喘。
- DOI:10.1007/s00408-016-9919-7
- 发表时间:2016
- 期刊:
- 影响因子:5
- 作者:Suresh,Karthik;Belchis,Deborah;Askin,Fred;Pearse,DavidB;Terry,PeterB
- 通讯作者:Terry,PeterB
Pleuropulmonary Kaposi Sarcoma in the Setting of Immune Reactivation.
免疫重新激活背景下的胸膜肺卡波西肉瘤。
- DOI:10.4172/2161-105x.1000352
- 发表时间:2016
- 期刊:
- 影响因子:0
- 作者:Suresh,Karthik;Semaan,Roy;Arias,Sixto;Karakousis,Petros;Lee,Hans
- 通讯作者:Lee,Hans
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Karthik Suresh其他文献
Karthik Suresh的其他文献
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{{ 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:
10295118 - 财政年份:2021
- 资助金额:
$ 5.53万 - 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:
10491235 - 财政年份:2021
- 资助金额:
$ 5.53万 - 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:
$ 5.53万 - 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:
$ 5.53万 - 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:
$ 5.53万 - 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:
$ 5.53万 - 项目类别:
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