Regulation of Lung Authopagy and Inflammation
肺自体解剖和炎症的调节
基本信息
- 批准号:8576134
- 负责人:
- 金额:$ 36.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-01 至 2017-03-31
- 项目状态:已结题
- 来源:
- 关键词:3-methyladenineAcuteAcute Lung InjuryAddressAdult Respiratory Distress SyndromeApoptosisAscaridilAttenuatedAutophagocytosisBiochemicalBlood VesselsBreathingChloroquineComplementary DNADataDevelopmentDiseaseDoseDown-RegulationEndothelial CellsEndotheliumEventGene DeliveryGeneticHeartIn VitroInflammationInflammatoryInjuryKnockout MiceLeadLinkLipopolysaccharidesLungLung InflammationMediatingMediator of activation proteinMolecularMolecular and Cellular BiologyMonitorMusPathogenesisPhysiologyPreventiveProcessProtein IsoformsPublishingRegulationRoleSignal PathwaySignal TransductionSirolimusSiteTestingTherapeuticThrombinTimeWorkaerosolizedbasein vivoinhibition of autophagyinhibitor/antagonistinsightinterdisciplinary approachloss of functionlung injurymouse modelnovelnovel therapeutic interventionnovel therapeuticsphospholipase C epsilonpublic health relevancereconstitutionresearch study
项目摘要
DESCRIPTION (provided by applicant): The overall objective of this application is to understand how autophagy and inflammation, particularly in the context of lung endothelium, are activated in association to control acute lung injury (ALI). The rationale for the study is based on our novel finding that phospholipase C epsilon (PLC¿), a bifunctional PLC isoform with primary sites of expression in the lung and heart, acts as a critical regulator of autophagy and inflammation in the lung and that inhibiting autophagy ameliorates LPS-induced lung vascular leak. Our published data and ongoing work show that mechanistic (formerly mammalian) target of rapamycin (MTOR), a known inhibitor of autophagy, also functions as endogenous modulator of EC inflammation. Furthermore, we have identified an important role of PLC¿ in causing down-regulation of MTOR levels in the lungs of mice challenged with LPS. Based on these findings, we propose to test the hypothesis that activation of endothelial PLC¿ down-regulates MTOR levels/signaling to induce autophagy in association with inflammation to cause ALI. Aim 1 will (i) ascertain the role of PLC¿ in mediating EC autophagy and inflammation, (ii) assess the contribution of autophagy to EC inflammation and apoptosis, (iii) determine the in vivo role of endothelial PLC¿ in causing lung inflammation and injury, and (iv) address the in vivo role of endothelial PLC¿ in causing lung autophagy and evaluate the contribution of this event in the mechanism of lung inflammation and injury. Aim 2 will (i) determine the role of PLC¿ in suppressing MTOR levels/signaling to cause EC autophagy and inflammation, (ii) determine the in vivo relevance of suppression of endothelial MTOR levels/signaling in causing lung vascular autophagy and inflammatory injury, and (iii) evaluate the therapeutic potential of autophagy inhibition against evolving ALI. These studies will utilize multidisciplinary approaches ranging from biochemical, cellular, and molecular biology to in vivo gene delivery and lung physiology, and take advantage of conditional PLC¿ and MTOR knockout mice. The creative integration of in vitro and in vivo studies will provide novel insights into the integrated regulation of EC autophagy and inflammation in ALI and may lead to novel therapeutic interventions to control ALI/ARDS.
描述(由申请人提供):本申请的总体目标是了解自噬和炎症(特别是在肺内皮的情况下)如何被激活以控制急性肺损伤(ALI)。该研究的基本原理是基于的。我们的新发现是磷脂酶 C epsilon (PLC¿) 是一种双功能 PLC 亚型,主要表达位点在肺和心脏,它是肺自噬和炎症的关键调节因子,并且抑制自噬可改善 LPS 诱导的肺血管渗漏。我们已发表的数据和正在进行的工作表明,雷帕霉素的机械靶标 (MTOR)(一种已知的自噬抑制剂)也可作为 EC 炎症的内源性调节剂。 PLC的重要作用??导致接受 LPS 攻击的小鼠肺部 MTOR 水平下调。基于这些发现,我们建议检验内皮 PLC 激活的假设。下调 MTOR 水平/信号传导以诱导与炎症相关的自噬,从而导致 ALI 目标 1 将 (i) 确定 PLC 的作用。介导 EC 自噬和炎症,(ii) 评估自噬对 EC 炎症和细胞凋亡的贡献,(iii) 确定内皮 PLC 的体内作用¿引起肺部炎症和损伤,以及 (iv) 解决内皮细胞 PLC 的体内作用¿目标 2 将 (i) 确定 PLC 的作用。抑制 MTOR 水平/信号传导导致 EC 自噬和炎症,(ii) 确定抑制内皮 MTOR 水平/信号传导导致肺血管自噬和炎症损伤的体内相关性,以及 (iii) 评估自噬抑制的治疗潜力这些研究将利用从生物化学、细胞和分子生物学到体内基因传递和肺生理学的多学科方法,并利用条件 PLC。体外和体内研究的创造性整合将为 ALI 中 EC 自噬和炎症的综合调节提供新的见解,并可能导致控制 ALI/ARDS 的新治疗干预措施。
项目成果
期刊论文数量(0)
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ARSHAD RAHMAN其他文献
ARSHAD RAHMAN的其他文献
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{{ truncateString('ARSHAD RAHMAN', 18)}}的其他基金
G-protein-induced Signaling of PMN-mediated Lung Injury
G 蛋白诱导的 PMN 介导的肺损伤信号转导
- 批准号:
6884889 - 财政年份:2002
- 资助金额:
$ 36.13万 - 项目类别:
G-protein-induced Signaling of PMN-mediated Lung Injury
G 蛋白诱导的 PMN 介导的肺损伤信号转导
- 批准号:
6786625 - 财政年份:2002
- 资助金额:
$ 36.13万 - 项目类别:
G-protein-induced Signaling of PMN-mediated Lung Injury
G 蛋白诱导的 PMN 介导的肺损伤信号转导
- 批准号:
6621506 - 财政年份:2002
- 资助金额:
$ 36.13万 - 项目类别:
G-protein-induced Signaling of PMN-mediated Lung Injury
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- 批准号:
7624162 - 财政年份:2002
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$ 36.13万 - 项目类别:
G-protein-induced Signaling of PMN-mediated Lung Injury
G 蛋白诱导的 PMN 介导的肺损伤信号转导
- 批准号:
7826830 - 财政年份:2002
- 资助金额:
$ 36.13万 - 项目类别:
G-protein-induced Signaling of PMN-mediated Lung Injury
G 蛋白诱导的 PMN 介导的肺损伤信号转导
- 批准号:
7473229 - 财政年份:2002
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$ 36.13万 - 项目类别:
G-protein-induced Signaling of PMN-mediated Lung Injury
G 蛋白诱导的 PMN 介导的肺损伤信号转导
- 批准号:
6434726 - 财政年份:2002
- 资助金额:
$ 36.13万 - 项目类别:
G-protein-induced Signaling of PMN-mediated Lung Injury
G 蛋白诱导的 PMN 介导的肺损伤信号转导
- 批准号:
7316663 - 财政年份:2001
- 资助金额:
$ 36.13万 - 项目类别:
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