Mechanobiology of Acinar Stability

腺泡稳定性的力学生物学

基本信息

批准号：
8182470
负责人：
VALERIE MARIE WEAVER
金额：
$ 71.2万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8182470
关键词：
Ablation Abnormal Cell Acinus organ component Adhesions Behavior Biological Biological Assay Biological Models Breast Cancer Diagnostics Cancerous Cell Adhesion Molecules Cell model Cells Chemicals Complex Coupled Cues Development Engineering Epithelial Cells Estrogens Exhibits Feedback Genetic Growth Factor Receptors Homeostasis Image Integrins Lasers Length Ligands Malignant Neoplasms Mammary gland Mechanics Mediating Membrane Glycoproteins Modeling Modification Molecular Molecular and Cellular Biology Morphogenesis Morphology Optics Plastics Property Proteins Receptor Signaling Signal Transduction Simulate Structure System Techniques Testing Therapeutic Tissue Model Tissues density malignant breast neoplasm millimeter nanoscale novel physical science progesterone receptor negative research study response tool tumor progression

项目摘要

In project two we explore how force regulates subcellular organization of adhesion molecules to promote acini morphogenesis. While a reductionist approach is typically used to clarify the molecular mechanisms that drive development and maintain homeostasis, we take the view that cell and tissue behavior are phenotypically plastic, mediated by adhesion and modified by mechanical force. We are testing the idea that force regulates the organization of proteins at the subcellular level to alter cellular organization at the tissue level but that emergent properties of multi cellular tissues and feedback mechanisms alter the responsiveness of cells to mechanical cues. We will test this idea by investigating the mechanisms by which mechanical force regulates acinar morphogenesis and stability. We will test whether force modulates integrin clustering, to drive fecal adhesions and enhance growth factor receptor signaling to modify acinar polarity and morphology. We will achieve this using cell biological approaches that assay signaling and acini behavior, through the use of engineered matrices and applied shear force and through PALM and TIRF imaging of integrin clustering and in response to modifications in cell surface glycoproteins, ligand density and cytoskeletal manipulations. We will also quantify how mechanical forces spread though 'normal' acinar structures te understand hew cells respond to and transmit forces within at tissue and investigate hew signaling mechanisms mediated through cell-cell and cell-ECM interactions synergize to regulate tissue homeostasis. This will be achieved by using biophysical techniques to mechanically perturb the system (AFM and subcellular laser ablation) and by then watching the system respond using genetically directed force-sensitive optical probes. Finally we will build models to test the concept that cells exhibit an integrated response to force and that this response is governed by emergent properties of multi cellular tissues. This will be achieved by modifying existing chemical-adhesion models and also building an integrated but simplified model, informed by molecular details, that simulates the whole system and that spans multiple spatial and temporal scales.

在第二个项目中，我们探讨了力如何调节粘附分子的亚细胞组织以促进acini形态发生。虽然简化主义方法通常用于阐明驱动发育并维持稳态的分子机制，但我们认为细胞和组织行为是表型塑性的，是由粘附介导的，并通过机械力进行了修饰。我们正在测试这样的想法，即强迫调节亚细胞水平的蛋白质组织在组织水平上改变细胞组织，但是多细胞组织的新兴特性和反馈机制改变了细胞对机械提示的反应性。我们将通过研究机械力调节腺泡形态发生和稳定性的机制来测试这一想法。我们将测试力是否调节整联蛋白聚类，驱动粪便粘附并增强生长因子受体信号传导以修饰腺泡极性和形态。我们将通过使用工程矩阵和施加的剪切力以及通过整合蛋白聚类的棕榈和TIRF成像，以及对细胞表面糖蛋白的修饰，配体密度和细胞骨架操纵的修饰，通过使用工程矩阵和施加的剪切力来分析信号传导和ACINI行为的细胞生物学方法来实现这一目标。我们还将量化机械力如何扩散，尽管“正常”的腺泡结构了解HEW细胞在组织内部响应并传递力，并研究通过细胞细胞和细胞ECM相互作用介导的HEW信号传导机制协同调节组织稳态。这将通过使用生物物理技术机械扰动系统（AFM和亚细胞激光消融）来实现这一目标，然后观察系统使用遗传定向的力敏感的光学探针响应。最后，我们将建立模型来测试细胞对力表现出综合响应的概念，并且该反应受多细胞组织的新兴特性的控制。这将通过修改现有的化学粘附模型，并构建一个综合但简化的模型，该模型通过分子细节告知，该模型模拟整个系统并跨越多个空间和时间尺度。