Defining the Mechanisms of Lymphatic Vascular Growth and Function
定义淋巴血管生长和功能的机制
基本信息
- 批准号:10365381
- 负责人:
- 金额:$ 55.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AmericanBindingBiochemicalBiological AssayBiomechanicsBlood VesselsBody FluidsChronicClinicalCoupledCyclic AMPCyclic AMP-Dependent Protein KinasesDataDefectDevelopmentDiseaseDominant-Negative MutationDysplasiaEnhancersEquilibriumEtiologyExposure toFDA approvedFundingG-Protein-Coupled ReceptorsGasesGene DeletionGene Expression ProfilingGeneticGrowthGrowth FactorHealthHumanImmune responseInflammationInterventionKnowledgeLeadLigationLipidsLymphangiogenesisLymphaticLymphatic DiseasesLymphatic Endothelial CellsLymphatic SystemLymphedemaMaintenanceMissionMolecularMusNeuropilin-2PathologicPathway interactionsPatientsPatternPhysiologicalPublic HealthRoleSignal PathwaySignal TransductionSphingosine-1-Phosphate ReceptorStimulusTestingTherapeuticUnited States National Institutes of HealthVascular Endothelial Growth Factor CVascular Endothelial Growth Factor Receptor-3Workadrenomedullinantagonistautocrinebasecalcitonin receptor-like receptorclinically relevantdrug repurposingeffective therapyhuman diseaseimprovedin vivoinsightlymphatic malformationslymphatic vasculaturelymphatic vesselmigrationmouse modelnegative affectnovel therapeutic interventionoverexpressionpeptide hormonereceptorreceptor expressionreceptor-activity-modifying proteinshear stresstherapeutic targettreatment strategywasting
项目摘要
PROJECT SUMMARY/ABSTRACT
Growth of lymphatic vessels from pre-existing vessels is achieved via lymphangiogenesis. The mechanisms that
control lymphangiogenesis remain incompletely understood. VEGF-C binding to, and activation of, its cognate
receptor VEGFR3 is the most well-studied pro-lymphangiogenic pathway known, and is necessary for the
formation, migration and proliferation of lymphatic endothelial cells (LECs). Indeed, humans and mice harboring
dominant negative mutations in VEGFR3 feature hypoplastic lymphatic vessels. In contrast, VEGF-C
overexpression in mice results in lymphatic vessel overgrowth and dysplasia. Hence, a delicate balance of
VEGF-C/VEGFR3 signaling is necessary for the proper patterning of the lymphatic vasculature. We have
identified laminar shear stress (LSS) as an enhancer of VEGF-C signaling. We have also identified the G protein-
coupled receptor (GPCR) sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) as an antagonist of VEGF-C
signaling that is enhanced by LSS. We will dissect the mechanisms by which LSS and S1PR1 regulate VEGF-
C signaling. We will also investigate the significance of this mechanism during health and disease by using
mouse models.
项目总结/摘要
通过淋巴管生成实现从预先存在的血管生长淋巴管。的机制
控制淋巴管生成仍然不完全清楚。VEGF-C与其同源物的结合和激活
受体VEGFR 3是已知的研究最充分的促淋巴管生成途径,并且是淋巴管生成所必需的。
淋巴管内皮细胞(LECs)的形成、迁移和增殖。事实上,人类和老鼠
VEGFR 3中的显性负突变以淋巴管发育不良为特征。相比之下,VEGF-C
小鼠中的过表达导致淋巴管过度生长和发育不良。因此,
VEGF-C/VEGFR 3信号传导对于淋巴管系统的适当模式化是必需的。我们有
确定层流剪切应力(LSS)作为VEGF-C信号传导的增强剂。我们还发现了G蛋白-
偶联受体(GPCR)鞘氨醇1-磷酸(S1 P)受体1(S1 PR 1)作为VEGF-C的拮抗剂
通过LSS增强的信令。我们将剖析LSS和S1 PR 1调节VEGF的机制。
C信号。我们还将通过使用
小鼠模型。
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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Rajanarayanan S Srinivasan其他文献
Rajanarayanan S Srinivasan的其他文献
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{{ truncateString('Rajanarayanan S Srinivasan', 18)}}的其他基金
Novel lymphatic genes that regulate heart valve development and disease
调节心脏瓣膜发育和疾病的新型淋巴基因
- 批准号:
10585707 - 财政年份:2022
- 资助金额:
$ 55.7万 - 项目类别:
Defining the Mechanisms of Lymphatic Vascular Growth and Function
定义淋巴血管生长和功能的机制
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10532232 - 财政年份:2016
- 资助金额:
$ 55.7万 - 项目类别:
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9194206 - 财政年份:2016
- 资助金额:
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