Mechanobiology of Epithelial Monolayers under Shear Loading

剪切载荷下单层上皮的力学生物学

• 批准号: 1834760
• 负责人: Beth Pruitt
• 金额: $ 57.07万
• 依托单位: University of California-Santa Barbara
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1834760&HistoricalAwards=false
• 关键词: Mechanobiology; Epithelial; Monolayers; under; Shear

Mechanical interactions between cells govern the basic processes of life. We don't understand these mechanical effects enough, however, to explain many of the important questions in multicellular biology, tissue development, and disease progression that we already know are dependent on intercellular forces. Maintenance and turnover of the attachments between cells (adhesions) is critical to how cells can form a barrier between different parts of organs. Adhesion is important to wound healing, and also disruption of cell-cell adhesion is a precursor to cancer metastasis. Organ formation, wound healing and cancer metastasis involve large deformations and force generation, yet the mechanisms underlying the dynamic regulation of cell adhesions, how cells slide or shear past one another, or how cell-cell adhesions function under mechanical loading are not yet understood. The research goal is to understand how tissues distribute and respond to shear force transmitted through cell-cell junctions. The project will test how shear modifies collective cell behavior and reorganization of cellular architecture. Such changes are coupled to the biomechanical properties of cells and ultimately regulate tissue integrity, barrier functions and homeostasis. The research results will be incorporated into modules for teaching basic Engineering and Biology courses, and the development of undergraduate research experiences within our laboratories. The PIs actively participate in community outreach and research experiences for teachers and under-represented students.This research combines custom micro-fabricated cell culture platforms with force-sensing and displacement-actuation with mechanical analyses and cell biological methods such as pharmacological inhibitors and knockout cell lines. We study how externally applied and cell-generated forces dynamically modify collective cell behavior in response to shear disruption. Physiological development exhibits slow deformations while injury occurs on a faster timescale, thus we test the idea that collective cell mechanoresponse depends not only on load and tissue rigidity, but also on the applied loading rate. We will test the idea that dynamic cell-cell adhesion is governed by protein catch bonds with force- and rate-dependence. This work will deliver new platform technologies for mechanical manipulation and observation of epithelial tissues and test new models of force transfer and cell-cell communications across cell-cell adhesions and the cytoskeleton. Insights gained in this work will increase our understanding of epithelial homeostasis which underlies normal barrier function in each organ system.

细胞之间的机械相互作用控制生命的基本过程。 但是，我们不够理解这些机械效应，无法解释我们已经知道的多细胞生物学，组织发育和疾病进展中的许多重要问题，这些问题取决于细胞间力。细胞之间的附着（粘附）之间的附件维护和周转对于细胞如何在器官之间形成屏障至关重要。 粘附对于伤口愈合很重要，并且细胞 - 细胞粘附的破坏也是癌症转移的前体。器官形成，伤口愈合和癌症转移涉及大变形和力产生，但是细胞粘附动态调节的机制，细胞如何滑动或剪切彼此滑动或剪切，或者在机械负荷下的细胞细胞粘附功能如何尚未理解。研究目标是了解组织如何分布和响应通过细胞 - 细胞连接传递的剪切力。 该项目将测试剪切方式如何修饰集体细胞行为和细胞结构的重组。这种变化与细胞的生物力学特性耦合，并最终调节组织完整性，障碍功能和稳态。 研究结果将纳入教授基础工程和生物学课程的模块中，以及我们实验室内的本科研究经验的发展。 PI为教师和代表性不足的学生积极参与社区外展和研究经验。这项研究将自定义的微型细胞培养平台与力传感和置换型分析与机械分析和细胞生物学方法（例如药理抑制剂和淘汰细胞系）结合在一起。我们研究外部应用和细胞生成的力如何响应剪切破坏而动态地改变集体细胞行为。生理发育表现出缓慢的变形，而损伤发生在更快的时间尺度上，因此我们测试了集体细胞机械响应不仅取决于负载和组织刚度，而且还取决于施加的负载速率。我们将测试动态细胞 - 细胞粘附受蛋白质捕获键的影响和速率依赖性的观念。这项工作将提供新的平台技术，用于对上皮组织的机械操纵和观察，并测试跨细胞细胞粘连和细胞骨架的力传递和细胞 - 细胞通信的新模型。在这项工作中获得的见解将增加我们对每个器官系统正常屏障功能的上皮稳态的理解。

项目成果

Controlled phage therapy by photothermal ablation of specific bacterial species using gold nanorods targeted by chimeric phages

• DOI: 10.1073/pnas.1913234117
• 发表时间: 2020-01-28
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Peng, Huan;Borg, Raymond E.;Chen, Irene A.
• 通讯作者: Chen, Irene A.

MEMS device for applying shear and tension to an epithelium combined with fluorescent live cell imaging

• DOI: 10.1088/1361-6439/abb12c
• 发表时间: 2020-12-01
• 期刊: JOURNAL OF MICROMECHANICS AND MICROENGINEERING
• 影响因子: 2.3
• 作者: Garcia，Miguel A.;Sadeghipour，Ehsan;Pruitt，Beth L.
• 通讯作者: Pruitt，Beth L.