Cortactin in Regulation of Pulmonary Vascular Permeability
Cortactin 调节肺血管通透性
基本信息
- 批准号:7618522
- 负责人:
- 金额:$ 38.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-05-01 至 2010-02-28
- 项目状态:已结题
- 来源:
- 关键词:Actin-Binding ProteinActinsAcuteAcute Lung InjuryAdhesivesAdult Respiratory Distress SyndromeAnimal ModelAsparagineAtomic Force MicroscopyCell ShapeCellsCessation of lifeCodeComplexCytoskeletonDNA Sequence RearrangementEMS1 geneEndothelial CellsEquilibriumExtravasationGenerationsIn VitroInflammationInflammatoryInjuryLaboratoriesLinkLiquid substanceLungMembraneMembrane MicrodomainsModelingMolecular BiologyMolecular Biology TechniquesMolecular TargetMutationPatientsPeripheralPermeabilityPhasePredispositionProtein ArrayProteinsProteomicsRecoveryRegulationResearch PersonnelResolutionRoleSepsisSerineSignal TransductionSingle Nucleotide PolymorphismSmall Interfering RNAStructureSyndromeTechniquesThrombinTransgenic AnimalsVariantVascular PermeabilitiesWorkbasehuman EMS1 proteinin vitro Modelin vivonovelprogramspulmonary vascular permeabilitytherapeutic targettooltranslational approach
项目摘要
DESCRIPTION (provided by applicant): The Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is a devastating consequence of systemic inflammatory conditions such as sepsis that afflicts almost 200,000 people a year in the US with 75,000 deaths. The hallmark of ALI is inflammation-induced disruption of the endothelial cell (EC) barrier that lines the pulmonary vasculature, resulting in leakage of fluid, protein, and cells into the airspaces of the lung. Our laboratory has extensively studied the mechanisms involved in maintaining and enhancing EC barrier function as a tool for identifying possible therapeutic targets. The current paradigm of EC barrier regulation suggests a balance exists between barrier-disrupting cellular contractile forces and barrier-protective cell-cell and cell-matrix tethering forces. Both competing forces in this model are intimately linked to the actin-based endothelial cytoskeleton by a variety of actin-binding proteins. Our work has defined an essential role for the actin-binding protein, cortactin, in the resolution phase of vascular permeability with this critical function occurring via EC cytoskeletal rearrangement. Very little is known about the mechanisms governing recovery of EC barrier function following injury. Thus, cortactin is an attractive molecular target for novel therapies and warrants the intense structure/function studies we propose in this application. With this background, the PI proposes to investigate the hypothesis that cortactin regulates EC cytoskeletal rearrangements that result in altered barrier function during ALI syndromes. In SA#1 we will mechanistically characterize the key portions of the cortactin molecule involved in barrier regulation through the use of molecular biology and proteomic techniques utilizing in vitro models of barrier disruption (e.g., thrombin, TGFpl) to focus on cortactin's role during the barrier recovery phase. Transgenic animal models of ALI will extend these studies in vivo. In SA#2 we will examine the role of cortactin in cortical actin and junctional protein rearrangements that regulate pulmonary endothelial barrier function using novel atomic force microscopy (AFM) and other techniques to functionally characterize cortactin's role in peripheral cytoskeletal rearrangements involved in barrier recovery, focusing on cortical actin structures, junctional complex formation, and lipid raft signaling. In SA#3 we will characterize the functional consequences of an ALI- associated coding single nucleotide polymorphism (SNP) we have identified in the cortactin gene through a combination of molecular biology and proteomic techniques. This aim will determine the mechanistic effects of this ALI-associated SNP on cortactin function as it pertains to endothelial permeability and barrier recovery using the in vitro and transgenic animal techniques described above.
描述(由申请人提供):急性肺损伤/急性呼吸窘迫综合征(ALI/ARDS)是全身性炎症状况的毁灭性后果,例如败血症,在美国每年遭受近200,000人死亡,死亡75,000人。 ALI的标志是炎症引起的内皮细胞(EC)屏障的破坏,该屏障将肺脉管系统排列,从而导致液体,蛋白质和细胞泄漏到肺部的飞机中。我们的实验室已广泛研究了维持和增强EC屏障功能的机制,作为确定可能的治疗靶标的工具。当前的EC屏障调节范式表明,屏障破坏细胞收缩力与屏障保护细胞细胞和细胞矩阵链接力之间存在平衡。该模型中的两个竞争力都与各种肌动蛋白结合蛋白与基于肌动蛋白的内皮细胞骨架有着密切的联系。我们的工作定义了肌动蛋白结合蛋白Cortactin在血管通透性的分辨率阶段的重要作用,并通过EC细胞骨架重排发生这种关键功能。关于受伤后恢复EC屏障功能的恢复的机制,知之甚少。因此,皮质素是新疗法的有吸引力的分子靶标,并保证我们在本应用中提出的强烈结构/功能研究。在这种背景下,PI提出了这样的假设,即cortactin调节EC细胞骨架重排,从而导致ALI综合症期间屏障功能改变。在SA#1中,我们将通过使用分子生物学和蛋白质组学技术的使用,利用屏障破坏的体外模型(例如,凝血酶,TGFPL)专注于皮质素在障碍恢复阶段中的作用,通过使用分子生物学和蛋白质组学技术来涉及屏障调节的皮质素分子的关键部分。 ALI的转基因动物模型将在体内扩展这些研究。 In SA#2 we will examine the role of cortactin in cortical actin and junctional protein rearrangements that regulate pulmonary endothelial barrier function using novel atomic force microscopy (AFM) and other techniques to functionally characterize cortactin's role in peripheral cytoskeletal rearrangements involved in barrier recovery, focusing on cortical actin structures, junctional complex formation, and lipid raft信号。在SA#3中,我们将通过分子生物学和蛋白质组学技术的组合在Cortactin基因中鉴定出在Cortactin基因中鉴定的单一核苷酸多态性(SNP)的功能后果。该目标将确定这种Ali相关SNP对皮质素功能的机械作用,因为它使用上述体外和转基因动物技术与内皮渗透性和屏障恢复有关。
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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STEVEN M DUDEK其他文献
STEVEN M DUDEK的其他文献
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{{ truncateString('STEVEN M DUDEK', 18)}}的其他基金
Pathobiology of MRSA-induced Endothelial Permeability and Acute Lung Injury
MRSA 诱导的内皮通透性和急性肺损伤的病理学
- 批准号:
10608606 - 财政年份:2022
- 资助金额:
$ 38.38万 - 项目类别:
Fostering Academic Physician-Investigators Treating High Risk Populations
培养治疗高危人群的学术医师研究人员
- 批准号:
10647841 - 财政年份:2021
- 资助金额:
$ 38.38万 - 项目类别:
Fostering Academic Physician-Investigators Treating High Risk Populations
培养治疗高危人群的学术医师研究人员
- 批准号:
10459247 - 财政年份:2021
- 资助金额:
$ 38.38万 - 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
- 批准号:
10472480 - 财政年份:2019
- 资助金额:
$ 38.38万 - 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
- 批准号:
10700843 - 财政年份:2019
- 资助金额:
$ 38.38万 - 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
- 批准号:
9791769 - 财政年份:2019
- 资助金额:
$ 38.38万 - 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
- 批准号:
10198029 - 财政年份:2019
- 资助金额:
$ 38.38万 - 项目类别:
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