A single cell assay for tissue activity
组织活性的单细胞测定
基本信息
- 批准号:10831316
- 负责人:
- 金额:$ 16.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:ActomyosinApicalApoptosisAreaBasal CellBasic ScienceBiological AssayBiomechanicsBreast Epithelial CellsCadherinsCell divisionCell membraneCellsCellular AssayClinicalCollagen Type IVDevelopmentDiffuseDiseaseElasticityEnvironmentEpithelial CellsEpitheliumExtracellular MatrixFibronectinsFrequenciesGrantHomeostasisHumanIn SituIntercellular JunctionsInvadedLamininLateralLengthLiquid substanceMammary NeoplasmsMeasurementMeasuresMechanicsMembraneModelingMyoepithelial cellNeoplasm MetastasisNoiseOncogenesOrganoidsOutputP-CadherinPatientsPhase TransitionPhysiological ProcessesPlayProcessProductionPropertyRoleSolidSourceSurfaceSystemTissuesTractionTraction Force Microscopyassay developmentcancer cellcancer invasivenesscell behaviorcell transformationexosomeinterestmammary epitheliumneoplastic cellpolyacrylamide gelsprofessorprogramsresponsetumor microenvironmenttumor progressionwound healing
项目摘要
Abstract
This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-
23-045.
Fluctuations in the active biomechanical properties of cells are understudied, but evidence suggest they play a
critical role in both core physiological processes and in disease. For example, tissue phase transitions, from
elastic- to fluid-like (or jammed to unjammed) are thought to arise in part from increased noise in cell junctional
mechanics. These forces can also result in shedding of cellular material like exosomes. Both of these
processes play a central role in cancer progression, most notably in invasion and metastasis. However, a
major challenge is identifying the specific subcellular origin of these forces and the machinery responsible for
them. For example, studies of tissue fluidization using vertex modeling approaches have defined the necessary
and sufficient geometric changes for tissue fluidization in epithelia. Specifically, active fluctuations in cell
junction length are required for the T1 transitions that change junctional topology and allow cells to diffuse like
a fluid. Actomyosin dynamics can drive these transition in the absence of cell division and apoptosis, but these
models focus on actomyosin activity at apical/lateral interfaces (between cells), but largely ignore more indirect
sources of activity, for example deriving from tractions generated at the basal surface which acts to sheer
lateral and apical cell junctions. By tracking the dynamics of single cells in both normal and transformed
primary human mammary epithelial organoids we see evidence that the activity necessary to fluidize a tissue
derives from interactions between cells and their basal interface at the ECM. At the single cell level, we reason
that this activity manifests as fluctuations in cell tractions, specifically at basal cell-ECM interfaces, and at the
tens of minutes timescale. In this supplemental proposal, we will first develop a platform allowing the
measurement of dynamic cell tractions at the cell-ECM interface which we will apply to single normal and
transformed mammary epithelial cells. Second, we will develop a parallel assay for measuring cell tractions at
the cell-cell interface. We hypothesize that the magnitude of fluctuations at the cell-ECM interface will be
several fold higher than at lateral interfaces, and that the largest fluctuations will occur at the tens of minutes
timescale, consistent with that of junctional fluctuations in intact tissues. Successful development of this assay
will allow us to investigate the impact of mechanical fluctuations in processes spanning tissue fluidization,
cancer cell invasions, and exosome shedding.
摘要
本申请是为了响应被标识为NOT-CA的特别利益通知(NOSI)而提交的-
23-045.
细胞活跃的生物力学特性的波动还没有得到充分的研究,但有证据表明,它们在细胞的生长过程中起着重要的作用。
在核心生理过程和疾病中起着关键作用。例如,组织相变,从
弹性到流体状(或堵塞到未堵塞)被认为部分是由于细胞连接处的噪音增加而引起的。
力学这些力也可以导致细胞物质如外来体的脱落。这两
过程在癌症进展中起核心作用,最显著的是在侵袭和转移中。但
主要的挑战是确定这些力量的特定亚细胞起源和负责这些力量的机制。
他们例如,使用顶点建模方法的组织流化研究已经定义了必要的
以及足够的几何变化以用于上皮中的组织流化。具体来说,细胞中的活跃波动
T1转变需要结长,T1转变改变结拓扑并允许细胞扩散,
流体。肌动球蛋白动力学可以在没有细胞分裂和凋亡的情况下驱动这些转变,但这些转变可能是由肌动球蛋白动力学引起的。
模型集中在顶端/侧面界面(细胞之间)的肌动球蛋白活性,但在很大程度上忽略了更间接的
活动源,例如源自基底表面处产生的牵引力,
侧和顶细胞连接。通过跟踪正常和转化细胞中单细胞的动态,
我们看到了证据表明,人类乳腺上皮类器官的活性,
来源于细胞与其ECM基底界面之间的相互作用。在单细胞水平上,我们推理
这种活性表现为细胞牵引力的波动,特别是在基底细胞-ECM界面,以及在细胞膜上。
几十分钟的时间尺度。在这项补充建议中,我们会首先发展一个平台,
测量细胞-ECM界面处的动态细胞牵引力,我们将其应用于单个正常和
转化的乳腺上皮细胞。其次,我们将开发一种平行测定法,用于测量细胞牵引力,
细胞-细胞界面。我们假设细胞-ECM界面的波动幅度将是
几倍高于横向接口,最大的波动将发生在几十分钟,
时间尺度,与完整组织中的连接波动一致。本试验的成功开发
将使我们能够研究机械波动在组织流化过程中的影响,
癌细胞入侵和外泌体脱落。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Organoid models for mammary gland dynamics and breast cancer.
- DOI:10.1016/j.ceb.2020.05.003
- 发表时间:2020-10
- 期刊:
- 影响因子:7.5
- 作者:Srivastava V;Huycke TR;Phong KT;Gartner ZJ
- 通讯作者:Gartner ZJ
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{{ truncateString('ANDREI GOGA', 18)}}的其他基金
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