Mechanobiology of Acinar Stability

腺泡稳定性的力学生物学

• 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
• 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

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.

在项目二中，我们探索力如何调节粘附分子的亚细胞组织以促进腺泡形态发生。虽然还原论方法通常用于阐明驱动发育和维持稳态的分子机制，但我们认为细胞和组织行为具有表型可塑性，由粘附介导并由机械力改变。我们正在测试这样的想法，即力在亚细胞水平上调节蛋白质的组织，从而改变组织水平上的细胞组织，但多细胞组织和反馈机制的新兴特性会改变细胞对机械线索的反应性。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检验这个想法。我们将测试力是否调节整合素聚类，以驱动粪便粘附并增强生长因子受体信号传导以改变腺泡极性和形态。我们将使用分析信号传导和腺泡行为的细胞生物学方法来实现这一目标，通过使用工程基质和施加剪切力，通过整合素聚类的 PALM 和 TIRF 成像，以及响应细胞表面糖蛋白、配体密度和细胞骨架操作的修饰。我们还将量化机械力如何通过“正常”腺泡结构传播，以了解细胞对组织内力的响应和传递，并研究通过细胞-细胞和细胞-ECM 相互作用介导的信号传导机制，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 和亚细胞激光烧蚀），然后使用遗传定向力敏感光学探针观察系统响应来实现。最后，我们将建立模型来测试细胞对力表现出综合反应的概念，并且这种反应受多细胞组织的新兴特性控制。这将通过修改现有的化学粘附模型并建立一个集成但简化的模型来实现，该模型以分子细节为基础，模拟整个系统并跨越多个空间和时间尺度。