Symmetry breaking and polarization of cell in 3D environments

3D 环境中细胞的对称性破缺和极化

基本信息

批准号：
9049973
负责人：
Kevin Michael Dean
金额：
$ 5.88万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9049973
关键词：
Actins Actomyosin Acute Address Adhesions Adopted Affect Animal Model Anisotropy Apoptosis Architecture Biochemical Biological Biological Process Biosensor Bundling Cell Differentiation process Cell Polarity Cell Shape Cell membrane Cell physiology Cell surface Cells Cellular Morphology Cellular biology Characteristics Collagen Collagen Fiber Complex Computer Vision Systems Coupling Cues Cytoskeleton Data Disease Embryonic Development Environment Event Evolution Extracellular Matrix F-Actin Family Feedback Fiber Fluorescence Fluorescence Resonance Energy Transfer Focal Adhesions Foundations Future Guanosine Triphosphate Phosphohydrolases Health Human Image Imaging technology Integrins Light Maintenance Maps Mechanics Mediating Mesenchymal Microfilaments Microscope Microscopy Molecular Neoplasm Metastasis Outcome Physiological Postdoctoral Fellow Primary Neoplasm Process Psychological reinforcement Radial Reporting Research Resistance Resolution Scientist Signal Transduction Site Staging Structure Testing Tissues Training Work cell motility clinically significant depolymerization extracellular insight live cell imaging migration novel polarized cell polymerization public health relevance reconstitution response rho single molecule spatiotemporal three dimensional structure three-dimensional modeling

项目摘要

DESCRIPTION (provided by applicant): The mechanics, 3D structure, and biochemical composition of the extracellular matrix (ECM) significantly influences diverse biological outcomes, including cellular polarization, differentiation, apoptosis, migration, and proliferation For example, ECM alignment triggers polarized cell morphologies and facilitates migration away from the primary tumor. However, it remains poorly understood how cells spatiotemporally integrate 3D ECM cues in order to selectively orchestrate downstream signaling. The objective of the proposed research here aims to further our understanding this process. Specifically, I will investigate how mesenchymal cells spontaneously establish anteroposterior cell polarity in 3D ECM environments. Towards these means, I will evaluate the spatiotemporal evolution of cell-collagen interfaces, integrin activation, Rho family GTPase signaling, and cytoskeletal dynamics, in mesenchymal cells undergoing 3D polarization. I hypothesize that ECM fibers oriented normal to the cell surface will trigger integrin clustering and the formation of mature matrix adhesions (Aim 1). Furthermore, I hypothesize that Rho family GTPase activation will be bifurcated into focal adhesion-dependent and independent regimes (Aim 2), and that this will result in ECM context-dependent modulation of actin polymerization, bundling, dendritic branching, actomyosin contraction, and depolymerization (Aim 3). This will be accomplished by light- sheet imaging of mesenchymal cells embedded within reconstituted ECM-like environments, acute pharmacological perturbations, and computer vision analysis of ECM fiber orientation, cell shape, signal transduction, and cytoskeletal dynamics. This research will serve as the foundation from which further studies can evaluate 3D spatiotemporal cell signaling in physiological and pathophysiological ECM states.

描述（由适用提供）：细胞外基质（ECM）的机械，3D结构和生化组成显着影响潜水的生物学结果，包括细胞极化，分化，凋亡，迁移和增殖，例如ECM对齐触发触发细胞形态和偏离小学的迁移。然而，它仍然鲜为人知的是细胞如何在空间整合3D ECM提示以选择性地编排下游信号传导。这里提出的研究的目的旨在进一步理解这一过程。具体而言，我将研究Messedectymal细胞如何在3D ECM环境中赞助建立前后细胞极性。在这些手段方面，我将在3D极化的间充质细胞中评估细胞胶原界面，整联蛋白激活，Rho家族GTPase信号传导和细胞骨架动力学的时空演化。我假设以ECM为导向的ECM纤维正常与细胞表面触发整合素聚类和成熟基质粘合剂的形成（AIM 1）。此外，我假设Rho家族GTPase激活将分为局灶性粘附依赖性和独立的方案（AIM 2），这将导致ECM上下文依赖于肌动蛋白聚合，束，树突，树突分支，Actomyosin protaction和AIM 3）的肌动蛋白聚合调节。这将通过嵌入重组的ECM样环境中的间充质细胞的光片成像，急性药物扰动以及ECM纤维纤维方向，细胞形状，信号翻译和细胞骨架动力学的计算机视觉分析。这项研究将是进一步研究可以评估物理和病理生理ECM状态中3D时空细胞信号传导的基础。