Molecular mechanisms initiating cell migrations in Caonorhabditis elegans
秀丽隐杆线虫细胞迁移的分子机制
基本信息
- 批准号:8867252
- 负责人:
- 金额:$ 33.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-15 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAdhesionsAnimal ModelApicalBasement membraneBasic ScienceBiochemistryBiological MarkersBiological ModelsCaenorhabditis elegansCell AdhesionCell PolarityCell Surface ReceptorsCell membraneCell physiologyCellsCellular StructuresColon CarcinomaColorectal CancerCommunicationComplexCytoskeletonDefectDependenceDevelopmentDiseaseDisseminated Malignant NeoplasmECM receptorEmbryoEmbryonic DevelopmentEphrinsEpidermisEpithelialEpithelial CellsF-ActinFailureFundingGTPase-Activating ProteinsGenesGeneticGenetic ScreeningGoalsGrowthGuanosine Triphosphate PhosphohydrolasesHandHealthHeart DiseasesHomologous GeneHumanHuman DevelopmentKnock-outLaboratoriesMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateMalignant neoplasm of urinary bladderMetastatic breast cancerModelingMolecularMonomeric GTP-Binding ProteinsMorphogenesisMuscleMuscle CellsMutationNeoplasm MetastasisPhenotypePlayProcessProteinsRecruitment ActivityRegulationResearch DesignRoleSignal PathwaySignal TransductionStructureSystemTestingTissuesTransgenesVesicleWorkanticancer researchaxonal guidanceblastomere structurecell motilityclinically relevantextracellularhuman diseasein vivoin vivo Modelmetastatic colorectalmigrationmutantnull mutationpreventreceptortraffickingtriple-negative invasive breast carcinomatumor progression
项目摘要
DESCRIPTION (provided by applicant): Cancer progression and metastasis require changes in cell polarity that drives changes in cellular adhesion and motility. Adhesion and motility are regulated by the polarized actin cytoskeleton. Our long-term goal is to identify the mechanisms that polarize actin during healthy growth and during disease. We have used the model organism C. elegans to study cell movements during embryonic development. Using knockout mutants we have shown that loss of regulators of actin nucleation including the GTPase CED-10/Rac1, any component of the actin nucleating Arp2/3 complex, or of its activator, the WAVE/SCAR complex, results in the same phenotype: failure in embryonic cell migrations, morphogenesis and altered epithelial polarity. Mutations in the conserved WAVE/SCAR complex are associated with cancers including aggressive metastatic cancers. For example, WAVE2 is misexpressed in malignant lung cancers and metastatic colorectal cancers (Semba et al. 2006; Iwaya et al. 2007). However, how the actin cytoskeleton is regulated during normal growth or misregulated during metastasis is not well understood. We have recently identified extracellular signals that regulate Rac1/CED-10 and WAVE/SCAR during embryonic cell migrations. With these upstream signals in hand we want to address the following hypothesis for how outside signals polarize F-actin: Objective/Hypothesis: We hypothesize that distinct signals at the plasma membrane activate the WAVE/SCAR complex to promote cell polarization, and that the extracellular receptors we have identified play an important role in both signaling between cells, and in transmitting signals intracellularly to polarize cellular F-actin. Specific Aims: (1) To tes the model that ECM (extra cellular matrix) receptors support epithelial cell migrations by regulating WAVE at the apical junction. (2) To determine if signaling between tissues organizes F-actin in epidermal cells. (3) To test the model that ECM receptors act through the regulation of specific Rac GAPs. Study Design: In Aim 1 we use our in vivo system to determine both how WAVE is recruited to apical junction and what role it plays there to better understand how WAVE/SCAR promotes cell polarity. In Aim 2 we create an in vivo model for testing how tissues detect the polarized state of F-actin in neighboring tissues. In Aim 3 we use genetics and biochemistry to identify the GAP proteins that regulate Rac/CED-10 during embryonic morphogenesis. Clinical relevance: The human homolog of one of the genes we study in C. elegans, WAVE3, is considered a biomarker for high grade, triple negative breast cancer (Kulkarni et al., 2012) and is associated with invasive prostate and colon cancers (Fernando et al., 2010; Zhang et al., 2012). Understanding the molecules that regulate actin dynamics through the WAVE/SCAR complex during cell migrations will not only enlighten our understanding of normal development but could suggest new biomarkers for altered actin regulation in human disease.
描述(由申请人提供):癌症进展和转移需要细胞极性的变化,从而驱动细胞粘附和运动性的变化。粘附和运动性由极化的肌动蛋白细胞骨架调节。我们的长期目标是确定在健康生长和疾病期间,hepactin的机制。我们使用了模式生物C。elegans研究胚胎发育过程中的细胞运动。使用敲除突变体,我们已经表明,肌动蛋白成核调节剂(包括GTPase CED-10/Rac 1、肌动蛋白成核Arp 2/3复合物的任何组分或其激活剂WAVE/SCAR复合物)的缺失会导致相同的表型:胚胎细胞迁移失败、形态发生和上皮极性改变。保守的WAVE/SCAR复合物中的突变与癌症相关,包括侵袭性转移性癌症。例如,WAVE 2在恶性肺癌和转移性结肠直肠癌中错误表达(Semba et al.2006; Iwaya et al.2007)。然而,肌动蛋白细胞骨架在正常生长过程中是如何调节的,在转移过程中是如何失调的,还没有很好的了解。我们最近确定了在胚胎细胞迁移过程中调节Rac 1/CED-10和WAVE/SCAR的细胞外信号。有了这些上游信号在手,我们想解决以下假设如何外部信号的F-actin:目的/假设:我们假设,在质膜不同的信号激活的WAVE/SCAR复合物,以促进细胞极化,和细胞外受体,我们已经确定发挥了重要作用,在两个细胞之间的信号,并在细胞内传输信号到细胞外的F-actin。具体目标:(1)建立细胞外基质(extra cellular matrix,ECM)受体通过调控WAVE支持上皮细胞迁移的模型。(2)确定组织之间的信号传导是否组织表皮细胞中的F-肌动蛋白。(3)为了验证ECM受体通过调节特定Rac GAP起作用的模型。研究设计:在目标1中,我们使用我们的体内系统来确定WAVE如何被招募到顶端连接以及它在那里扮演什么角色,以更好地理解WAVE/SCAR如何促进细胞极性。在目标2中,我们创建了一个体内模型,用于测试组织如何检测邻近组织中F-肌动蛋白的极化状态。在目标3中,我们使用遗传学和生物化学来鉴定在胚胎形态发生期间调节Rac/CED-10差距蛋白。临床相关性:我们在C.秀丽隐杆线虫WAVE 3被认为是高级别三阴性乳腺癌的生物标志物(Kulkarni等人,2012)并且与侵袭性前列腺癌和结肠癌相关(Fernando et al.,2010; Zhang等人,2012年)。了解在细胞迁移过程中通过WAVE/SCAR复合物调节肌动蛋白动力学的分子不仅会启发我们对正常发育的理解,而且可能为人类疾病中改变的肌动蛋白调节提供新的生物标志物。
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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Martha C Soto其他文献
Martha C Soto的其他文献
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{{ truncateString('Martha C Soto', 18)}}的其他基金
Laser Spinning Disc Confocal System for live-cell and live-organism microscopy
用于活细胞和活有机体显微镜的激光转盘共焦系统
- 批准号:
8243974 - 财政年份:2012
- 资助金额:
$ 33.39万 - 项目类别:
Mechanism of ECM regulation of actin nucleation during morphogenesis.
形态发生过程中 ECM 调节肌动蛋白成核的机制。
- 批准号:
8296622 - 财政年份:2009
- 资助金额:
$ 33.39万 - 项目类别:
Molecular mechanisms initiating cell migrations in Caonorhabditis elegans
秀丽隐杆线虫细胞迁移的分子机制
- 批准号:
10642919 - 财政年份:2009
- 资助金额:
$ 33.39万 - 项目类别:
Mechanism of ECM regulation of actin nucleation during morphogenesis.
形态发生过程中 ECM 调节肌动蛋白成核的机制。
- 批准号:
8104281 - 财政年份:2009
- 资助金额:
$ 33.39万 - 项目类别:
Molecular mechanisms initiating cell migrations in Caonorhabditis elegans
秀丽隐杆线虫细胞迁移的分子机制
- 批准号:
9305063 - 财政年份:2009
- 资助金额:
$ 33.39万 - 项目类别:
Molecular mechanisms initiating cell migrations in Caonorhabditis elegans
秀丽隐杆线虫细胞迁移的分子机制
- 批准号:
10249352 - 财政年份:2009
- 资助金额:
$ 33.39万 - 项目类别:
Mechanism of ECM regulation of actin nucleation during morphogenesis.
形态发生过程中 ECM 调节肌动蛋白成核的机制。
- 批准号:
7893597 - 财政年份:2009
- 资助金额:
$ 33.39万 - 项目类别:
Molecular mechanisms initiating cell migrations in Caonorhabditis elegans
秀丽隐杆线虫细胞迁移的分子机制
- 批准号:
8703847 - 财政年份:2009
- 资助金额:
$ 33.39万 - 项目类别:
Molecular mechanisms initiating cell migrations in Caonorhabditis elegans
秀丽隐杆线虫细胞迁移的分子机制
- 批准号:
10796184 - 财政年份:2009
- 资助金额:
$ 33.39万 - 项目类别:
Mechanism of ECM regulation of actin nucleation during morphogenesis.
形态发生过程中 ECM 调节肌动蛋白成核的机制。
- 批准号:
8499354 - 财政年份:2009
- 资助金额:
$ 33.39万 - 项目类别:
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