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:8703847
- 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 PhosphohydrolasesHandHeart DiseasesHomologous GeneHumanHuman DevelopmentKnock-outLaboratoriesMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateMalignant neoplasm of urinary bladderMetastatic toModelingMolecularMonomeric GTP-Binding ProteinsMorphogenesisMuscleMuscle CellsMutationNeoplasm MetastasisPhenotypePlayProcessProteinsRecruitment ActivityRegulationResearch DesignRoleSignal PathwaySignal TransductionStructureSystemTestingTissuesTransgenesVesicleWorkanticancer researchaxonal guidanceblastomere structurecell motilityclinically relevantextracellularhuman diseasein vivoin vivo Modelmalignant breast neoplasmmetastatic colorectalmigrationmutantnull mutationpreventpublic health relevancereceptortraffickingtriple-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):癌症的进展和转移需要细胞极性的变化,以驱动细胞粘附和运动的变化。粘附和运动性受偏振肌动蛋白细胞骨架调节。我们的长期目标是确定健康生长和疾病期间肌动蛋白两极的机制。我们已经使用模型有机体秀丽隐杆线虫在胚胎发育过程中研究细胞运动。使用基因敲除突变体,我们已经表明,肌动蛋白成核调节剂的损失,包括GTPase Ced-10/Rac1,肌动蛋白成核的ARP2/3复合物的任何成分,或其其激活剂,波动/疤痕复合物,导致相同的表型:相同的表型:胚胎细胞迁移,形态学和改变的胚胎细胞迁移,形态学和改变的上皮性。保守波/疤痕复合物中的突变与包括侵袭性转移性癌症在内的癌症有关。例如,Wave2在恶性肺癌和转移性结直肠癌中被敏感(Semba等,2006; Iwaya等,2007)。但是,在正常生长期间如何调节肌动蛋白细胞骨架或转移期间不正当调节。我们最近确定了在胚胎细胞迁移过程中调节Rac1/CED-10和波/疤痕的细胞外信号。借助这些上游信号,我们想解决外部信号如何极化F-肌动蛋白的两极分化的假设:客观/假设:我们假设质膜上的不同信号激活了波/疤痕复合物以促进细胞极化,而细胞外受体我们已经在细胞之间识别出频段的信号在跨性别范围内,并且在跨性别范围内识别出重要的作用。具体目的:(1)要通过调节顶端连接处的波来支持ECM(额外的细胞基质)受体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在表皮细胞中组织F-肌动蛋白。 (3)测试ECM受体通过调节特定RAC间隙作用的模型。研究设计:在AIM 1中,我们使用我们的体内系统来确定如何募集波顶连接以及在那里扮演什么作用,以更好地了解波/疤痕如何促进细胞极性。在AIM 2中,我们创建了一个体内模型,用于测试组织如何检测相邻组织中F-肌动蛋白的极化状态。在AIM 3中,我们使用遗传学和生物化学来鉴定在胚胎形态发生过程中调节RAC/CED-10的间隙蛋白。临床相关性:我们在秀丽隐杆线虫中研究的基因之一的人类同源物被认为是高级,三层阴性乳腺癌的生物标志物(Kulkarni等,2012),并且与浸润性前列腺和结肠癌有关(Fernando等人,2010; Zhang等,2012; Zhang et al。,2012)。了解在细胞迁移过程中通过波/疤痕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,而且可以暗示改变人类疾病中肌动蛋白调节的新生物标志物。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Martha C Soto其他文献
Martha C Soto的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
8867252 - 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:
相似国自然基金
时空序列驱动的神经形态视觉目标识别算法研究
- 批准号:61906126
- 批准年份:2019
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
本体驱动的地址数据空间语义建模与地址匹配方法
- 批准号:41901325
- 批准年份:2019
- 资助金额:22.0 万元
- 项目类别:青年科学基金项目
大容量固态硬盘地址映射表优化设计与访存优化研究
- 批准号:61802133
- 批准年份:2018
- 资助金额:23.0 万元
- 项目类别:青年科学基金项目
IP地址驱动的多径路由及流量传输控制研究
- 批准号:61872252
- 批准年份:2018
- 资助金额:64.0 万元
- 项目类别:面上项目
针对内存攻击对象的内存安全防御技术研究
- 批准号:61802432
- 批准年份:2018
- 资助金额:25.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Cytoskeleton-mediated regulation of insulin secretion hot spots in pancreatic beta cells
细胞骨架介导的胰腺β细胞胰岛素分泌热点的调节
- 批准号:
10679903 - 财政年份:2023
- 资助金额:
$ 33.39万 - 项目类别:
Elucidating the role of Myosin 5b in intestinal inflammation
阐明肌球蛋白 5b 在肠道炎症中的作用
- 批准号:
10883872 - 财政年份:2023
- 资助金额:
$ 33.39万 - 项目类别:
Diversity Supplement: Novel Role of Nephron Epithelialization in Nuclear Signaling
多样性补充:肾单位上皮化在核信号传导中的新作用
- 批准号:
10853534 - 财政年份:2023
- 资助金额:
$ 33.39万 - 项目类别:
Mechanical Modulation of Cell Migrations by DNA Nanoassemblies
DNA 纳米组件对细胞迁移的机械调节
- 批准号:
10659333 - 财政年份:2023
- 资助金额:
$ 33.39万 - 项目类别: