Cadherin Adhesion and Mechanosensing
钙粘蛋白粘附和机械传感
基本信息
- 批准号:8304691
- 负责人:
- 金额:$ 27.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-06-01 至 2016-02-29
- 项目状态:已结题
- 来源:
- 关键词:Actin-Binding ProteinActinsAddressAdhesionsAdultAttentionAustraliaBindingBiochemicalBiochemistryBiological ProcessBiologyBlood VesselsCadherinsCell Adhesion MoleculesCell NucleusCell ShapeCell Surface ReceptorsCell physiologyCell surfaceCell-Cell AdhesionCellsCellular biologyCollaborationsComplexCouplesDevelopmentEnvironmentEsthesiaEventExtracellular MatrixFelis catusGoalsGrantHealthHumanImageIntegrinsIntercellular JunctionsInterventionInvestigationIon ChannelMeasurementMechanicsMediatingMethodologyMoldsMolecularMorphogenesisMorphologyMovementMutationMyosin ATPaseMyosin Type IINeoplasm MetastasisPathway interactionsPhosphorylationPlayPositioning AttributeProtein IsoformsProteinsReagentResearchRoleSignal TransductionStressTechnologyTestingTissue EngineeringTissuesVinculinWound Healingbasecell typedirect applicationfluorescence imaginginnovationknock-downmedical schoolsmultidisciplinarynovelprogramssensortissue regenerationtool
项目摘要
DESCRIPTION (provided by applicant): This research expands on new and novel findings from this group that show definitively that cadherin complexes, essential cell-cell adhesion proteins in all cohesive tissues, are tension sensors that probe the mechanical environment of the cell to regulate a wide range of critical functions including morphogenesis, wound healing, tissue organization, and metastasis. Increasing evidence shows that crucial biological functions, in development and in adult tissues, are regulated by the mechanical environment, which couples to the cytoskeletal network and nucleus via cell surface adhesion proteins. Although integrins are well-established force sensors, our new findings show that cadherins are also critical mechanical and signaling hubs in tissues. In this program, we advance our initial investigations to elucidate the force-actuated, molecular cascades in the cadherin-specific mechanotransduction pathway. Our innovative combination of mechanical measurements and dynamic fluorescence imaging has substantial advantages over competing technologies because it enables the application of direct, controlled localized force to cadherin adhesions, while simultaneously imaging the rapid, early molecular events in mechanotransduction, in a high throughput format. By enhancing this methodology with powerful biochemical tools and complementary studies of the impact of endogenous contractile force on cell-cell junctions, we are strategically positioned to address fundamental, unresolved questions regarding mechanisms of force propagation through tissues. This proposed program will significantly advance our understanding of mechano-transduction in tissues, and pave the way towards our long-term goals of developing targeted therapies for metastasis or leaky blood vessels, and of enhancing tissue regeneration and wound healing.
PUBLIC HEALTH RELEVANCE: This proposed program expands on new findings from this group showing that cadherin complexes, which are crucial intercellular adhesion proteins in all cohesive tissues, sense mechanical force to regulate molecular and signaling cascades governing such functions as wound healing, morphogenesis, tissue regeneration, and metastasis. These studies will make major advances in the understanding of mechanisms by which force regulates cadherin-dependent functions, in the broader context of mechano-biology, and pave the way towards our long-term health related goals of developing targeted therapies for metastasis, leaky blood vessels, wound healing, and tissue regeneration.
描述(由申请人提供):这项研究扩展了该小组的新发现和新颖发现,明确表明钙粘蛋白复合物是所有粘性组织中必需的细胞-细胞粘附蛋白,是张力传感器,可探测细胞的机械环境以调节细胞的机械环境。广泛的关键功能,包括形态发生、伤口愈合、组织组织和转移。越来越多的证据表明,发育和成体组织中的关键生物功能受到机械环境的调节,机械环境通过细胞表面粘附蛋白与细胞骨架网络和细胞核耦合。尽管整合素是成熟的力传感器,但我们的新发现表明钙粘蛋白也是组织中关键的机械和信号中枢。 在这个项目中,我们推进了初步研究,以阐明钙粘蛋白特异性机械转导途径中力驱动的分子级联。我们的机械测量和动态荧光成像的创新组合比竞争技术具有显着优势,因为它能够对钙粘蛋白粘附施加直接、受控的局部力,同时以高通量格式对力转导中的快速、早期分子事件进行成像。通过利用强大的生化工具和内源收缩力对细胞-细胞连接影响的补充研究来增强这种方法,我们在战略上定位于解决有关通过组织的力传播机制的基本的、未解决的问题。该计划将显着增进我们对组织中机械传导的理解,并为我们开发针对转移或渗漏血管的靶向疗法以及增强组织再生和伤口愈合的长期目标铺平道路。
公共健康相关性:该计划扩展了该小组的新发现,表明钙粘蛋白复合物是所有粘性组织中至关重要的细胞间粘附蛋白,可感知机械力以调节分子和信号级联,从而控制伤口愈合、形态发生、组织再生等功能和转移。这些研究将在更广泛的力学生物学背景下,在理解力调节钙粘蛋白依赖性功能的机制方面取得重大进展,并为实现我们的长期健康相关目标铺平道路,即开发针对转移、漏血的靶向疗法血管、伤口愈合和组织再生。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Deborah E Leckband其他文献
Deborah E Leckband的其他文献
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