Regulation of endothelial cell invasion, migration and cell junction plasticity
内皮细胞侵袭、迁移和细胞连接可塑性的调节
基本信息
- 批准号:10685981
- 负责人:
- 金额:$ 39.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAdherens JunctionAffectBlood VesselsCell CommunicationCell-Cell AdhesionCellsCytoskeletonDevelopmentEndothelial CellsEndotheliumEngineeringEnvironmentEventExtracellular MatrixExtracellular Matrix DegradationFutureGoalsGrowth Factor ReceptorsIntegral Membrane ProteinIntercellular JunctionsInvadedKDR geneLaboratoriesLightLocationMediatingPermeabilityPhosphorylationPhysiologic NeovascularizationPhysiologicalProcessRegulationResearchRoleSignal TransductionSphingosine-1-Phosphate ReceptorStimulusStructureTherapeuticTimeVascular SystemWorkangiogenesiscadherin 5cell motilityhuman diseasemigrationnoveloptogeneticsspatiotemporalsrc-Family Kinasestool
项目摘要
Project Summary
One of the main research directions of my laboratory focuses on regulation of the endothelial barrier and
endothelial cell migration. These processes are critical for physiological function of vascular system and they
are often dysregulated in human diseases. A lot of progress has been made in understanding signaling that
regulates endothelial barrier and cell migration. However, stimulation of endothelial cell migration during
angiogenesis is a highly localized and transient event. Defining the role of the local and temporal components
of angiogenic signaling has been challenging due to limitations of current tools. Furthermore, spatiotemporal
regulation of the endothelial barrier by these stimuli has been poorly understood. Our proposed work will focus
on determining how the location and duration of migratory signals direct endothelial cell invasion and migration
through extracellular matrix, and how they affect the organization and permeability of the endothelial barrier.
The endothelial barrier is controlled at the level of adherens junctions (AJs), cell-cell adhesion structures
mediated by the transmembrane protein VE-cadherin. Phosphorylation-mediated signaling regulates the
structure and permeability of AJs. In our recent studies, we described a dual role of tyrosine kinase Src and its
phosphorylation of VE-cadherin in regulation of endothelial permeability. Our results demonstrated that Src-
mediated phosphorylation induces formation of dynamic AJs that still retain their barrier function. This suggests
a mechanism for the regulation of AJ plasticity that does not compromise barrier permeability during
endothelial cell migration. In parallel studies, we dissected a mechanism of Src-regulated degradation of the
extracellular matrix by the endothelial cell and discovered a novel cytoskeletal component that mediates
formation of matrix-degrading podosomes. The studies proposed here will continue to build on our previous
findings and focus on dissecting how phosphorylation of VE-cadherin and angiogenic signaling by Vascular
Growth Factor Receptor 2 (VEGFR2), Sphingosine-1-phosphate Receptor 1 (S1PR1), and Src regulate
plasticity of AJs as well as invasion and migration of endothelial cells. We will employ novel optogenetic tools
that will allow us to interrogate these processes with precise spatial and temporal control. We will use
engineered light-regulated VEGFR2, S1PR1, and Src to determine the effects of locally and temporally
controlled angiogenic signals and dissect mechanisms that mediate regulation of AJs and migration of
endothelial cells in three dimensional environment. Our long-term goal is to define the processes that control
migration of endothelial cells and endothelial barrier function during angiogenesis.
项目总结
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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ANDREI V KARGINOV其他文献
ANDREI V KARGINOV的其他文献
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{{ truncateString('ANDREI V KARGINOV', 18)}}的其他基金
Optogenetic Control of Tumor Initiation and Tumor Progression in vivo
体内肿瘤发生和进展的光遗传学控制
- 批准号:
10640927 - 财政年份:2022
- 资助金额:
$ 39.98万 - 项目类别:
Regulation of endothelial cell invasion, migration and cell junction plasticity
内皮细胞侵袭、迁移和细胞连接可塑性的调节
- 批准号:
10406685 - 财政年份:2022
- 资助金额:
$ 39.98万 - 项目类别:
Optogenetic Control of Tumor Initiation and Tumor Progression in vivo
体内肿瘤发生和进展的光遗传学控制
- 批准号:
10413468 - 财政年份:2022
- 资助金额:
$ 39.98万 - 项目类别:
Optogenetic tools for the dissection of oncogenic signaling mediated by kinases
用于解析激酶介导的致癌信号的光遗传学工具
- 批准号:
9891973 - 财政年份:2018
- 资助金额:
$ 39.98万 - 项目类别:
Src-mediated pathways regulating adherens junction assembly.
Src 介导的途径调节粘附连接组装。
- 批准号:
10166863 - 财政年份:2017
- 资助金额:
$ 39.98万 - 项目类别:
Src-mediated pathways regulating adherens junction assembly.
Src 介导的途径调节粘附连接组装。
- 批准号:
9310733 - 财政年份:2017
- 资助金额:
$ 39.98万 - 项目类别:
New methods for activation of kinases and kinase circuits in living cells.
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8243734 - 财政年份:2012
- 资助金额:
$ 39.98万 - 项目类别:
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