Modeling bi-directional signaling and cytoskeletal dynamics in 3D cell migrations
模拟 3D 细胞迁移中的双向信号传导和细胞骨架动力学
基本信息
- 批准号:9238742
- 负责人:
- 金额:$ 57.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-16 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAdhesionsAlternative SplicingAreaBiochemicalBiochemical PathwayBiological ProcessBiologyBiomechanicsBiophysicsCell CommunicationCell modelCell physiologyCell-Matrix JunctionCellsCellular StructuresComplexComputer SimulationCouplingCuesCytoskeletal ModelingDataDevelopmentDimensionsDiseaseEngineeringEnvironmentEpidermal Growth FactorEventExtracellular MatrixF-ActinFamilyGap JunctionsGoalsGrowth FactorIn VitroKineticsKnowledgeLightLung NeoplasmsMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of lungMammary NeoplasmsMechanicsMediatingMetastatic breast cancerMicrofluidicsModelingMolecularMotionMotor ActivityNatureNeoplasm MetastasisPathway interactionsPhysiologicalPhysiological ProcessesPlant RootsPopulation DynamicsProcessPrognostic MarkerPropertyProtein IsoformsProteinsQuantitative MicroscopyReceptor ActivationResearchRheologyRoleSignal TransductionStimulusSystemTestingTimeTranslatingTumor Cell InvasionWorkbasecell motilityclinically relevantcomputer studiescrosslinkexperimental studygenetic regulatory proteinimprovedin vivoinsightmalignant breast neoplasmmechanical forcemembermigrationmulti-scale modelingneoplastic cellnovelpatient biomarkersprognosticpublic health relevanceresponsesoundsuccesstherapeutic targettumor progressionvasodilator-stimulated phosphoproteinviscoelasticity
项目摘要
DESCRIPTION (provided by applicant): Cellular structure and function, in healthy and diseased systems, is regulated by the interaction of cells with the underlying and surrounding three-dimensional extra-cellular matrix. These complex biochemical and biomechanical interactions, independently, are well known to regulate tumor progression, invasion and metastasis. For example, the aberrant response of cells to biochemical and biophysical stimuli in metastatic breast cancer is often initiated by engagement of the cytoskeletal machinery. As such, actin interacting proteins are found at the nexus of signaling network crosstalk between biochemical and adhesion-promoting cues. One such example is Mena, a member of the Ena/VASP family of actin regulatory proteins, which has been characterized for aberrant cell-signaling response during invasion and metastasis. However, how the altered signaling network is translated into the mechanical processes, and how are these sub-cellular mechanical processes then converted into whole cell migration in 3D environments remain largely elusive. Here, based on our preliminary data, we hypothesize that increased tumor cell invasiveness in 3D environments, is governed by coupling aberrant molecular level signaling events to molecular, macromolecular and cellular biomechanical processes. Our primary goal in this proposal is to rigorously test our hypothesis by bridging the knowledge gap between in vitro signaling studies at the molecular level, and molecular mechanical and cellular models in 3D, and test the predictions of our models through quantitative experiments in 3D environments. We plan to develop and validate our cellular models using the following three specific aims: Aim I: Develop an integrated subcellular model of cytoskeletal viscoelasticity and intracellular signaling
in native like 3D matrices. Aim II: Develop a quantitative model of cell migration, in 3D matrices,
utilizing results from the subcellular model of Aim I. Aim III: Validate results of Aims I and II b quantifying how signaling acts cooperatively with cellular mechanics machinery and extracellular matrix properties to regulate cell migration in 3D. All three aims build upon strong preliminary data in both computation and experimental studies and will provide both fundamental insights into the coupling between mechanical and biochemical pathways and integration of information from sub-cellular structures to the cellular level. At the same time, the focus on 3D environments will create new and physiologically relevant knowledge about cellular systems in native like environments. Finally, novel platforms developed through this work will be able to test clinically relevant hypotheses and help in quantitatively understanding complex multi-scale processes during various stages of cancer progression.
描述(由申请人提供):在健康和患病系统中,细胞结构和功能是由细胞与底层和周围三维细胞外基质的相互作用调节的。众所周知,这些复杂的生物化学和生物力学相互作用独立地调节肿瘤的进展、侵袭和转移。例如,在转移性乳腺癌中,细胞对生化和生物物理刺激的异常反应通常是由细胞骨架机制的参与引起的。因此,肌动蛋白相互作用蛋白在生化和促进粘附的信号网络串扰的联系中被发现。其中一个例子是Mena,它是肌动蛋白调节蛋白Ena/VASP家族的成员,在侵袭和转移过程中具有异常的细胞信号反应。然而,改变的信号网络如何转化为机械过程,以及这些亚细胞机械过程如何转化为3D环境中的全细胞迁移,在很大程度上仍然是难以捉摸的。在这里,基于我们的初步数据,我们假设肿瘤细胞在3D环境中的侵袭性增加是由异常分子水平的信号事件与分子、大分子和细胞生物力学过程的耦合控制的。我们在本提案中的主要目标是通过弥合分子水平的体外信号研究与3D分子力学和细胞模型之间的知识差距来严格测试我们的假设,并通过3D环境中的定量实验来测试我们模型的预测。我们计划利用以下三个具体目标来开发和验证我们的细胞模型:目标一:开发细胞骨架粘弹性和细胞内信号传导的集成亚细胞模型
项目成果
期刊论文数量(18)
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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{{ truncateString('FRANK B GERTLER', 18)}}的其他基金
Dynamic Imaging of EMT in the Breast Cancer Microenvironment
乳腺癌微环境中EMT的动态成像
- 批准号:
9262882 - 财政年份:2013
- 资助金额:
$ 57.14万 - 项目类别:
Modeling bi-directional signaling and cytoskeletal dynamics in 3D cell migrations
模拟 3D 细胞迁移中的双向信号传导和细胞骨架动力学
- 批准号:
9036957 - 财政年份:2013
- 资助金额:
$ 57.14万 - 项目类别:
Modeling bi-directional signaling and cytoskeletal dynamics in 3D cell migrations
模拟 3D 细胞迁移中的双向信号传导和细胞骨架动力学
- 批准号:
8477823 - 财政年份:2013
- 资助金额:
$ 57.14万 - 项目类别:
Dynamic Imaging of EMT in the Breast Cancer Microenvironment
乳腺癌微环境中EMT的动态成像
- 批准号:
9105168 - 财政年份:2013
- 资助金额:
$ 57.14万 - 项目类别:
Modeling bi-directional signaling and cytoskeletal dynamics in 3D cell migrations
模拟 3D 细胞迁移中的双向信号传导和细胞骨架动力学
- 批准号:
8842951 - 财政年份:2013
- 资助金额:
$ 57.14万 - 项目类别:
Modeling bi-directional signaling and cytoskeletal dynamics in 3D cell migrations
模拟 3D 细胞迁移中的双向信号传导和细胞骨架动力学
- 批准号:
8652954 - 财政年份:2013
- 资助金额:
$ 57.14万 - 项目类别:
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