Integrative Approaches for Probing Cell Mechanotransduction in Health and Disease

探索健康和疾病中细胞力转导的综合方法

• 批准号: 10372327
• 负责人: John Tuan Ngo
• 金额: $ 34.09万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-23 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372327
• 关键词: Address; Adhesions; Biochemical; Biochemical Genetics; Biomechanics; Cells; Chemicals; Coupled; Critical Pathways; Cues; Development; Disease; Electron Microscopy; Environment; Event; Health; Integral Membrane Protein; Location; Mechanics; Mechanoreceptors; Molecular; Pathologic; Pathway interactions; Play; Process; Receptor Activation; Regulation; Role; Shapes; Signal Transduction; Source; Tissues; Work; design; experience; extracellular; high resolution imaging; human tissue; insight; light microscopy; mechanical force; mechanotransduction; notch protein; single molecule; synergism; tool

Project Summary Notch receptors are mechanically activated transmembrane proteins that play important roles in regulating cell fate, differentiation, proliferation, adhesion, and many other critical processes. However, the majority of studies to date have been focused largely on understanding Notch from biochemical and genetic perspectives, and only recently been explored as a mechanoreceptor. Given the varied roles Notch plays in both normal and pathological states, it is necessary to formulate an integrated mechano-chemical perspective of Notch signaling and regulation as such outlook is required to achieve a comprehensive view of this critical pathway. In this project, my lab will leverage our expertise in chemical probe development and molecular tool design in order to address sharply focused mechanistic questions regarding Notch mechanotransduction. In order to distinguish our contributions from those of others, we will pursue a multi-scale understanding of the pathway by combining single molecule studies and high-resolution imaging with the aim of understanding how the activation of the receptor is coupled to biomechanical events that occur within the cell. In particular, new correlative light and electron microscopy will be developed and applied to determine the precise timing and location of events surrounding Notch signal transduction. In addition, in order to address important questions regarding the source and magnitude of the external forces that are experienced by cells, we will also create synthetic versions of Notch and apply them as genetically encoded “tensiometers.” Successful execution of this work will provide deep insights into the synergy occurring between biochemical and mechanical cues as well as increase our overall understanding of the how cells sense and interpret mechanical information.

项目概要 Notch受体是机械激活的跨膜蛋白，在调节细胞中发挥重要作用 命运、分化、增殖、粘附和许多其他关键过程。然而，大多数研究 迄今为止，人们主要集中于从生化和遗传角度理解Notch，并且只 最近被探索作为机械感受器。鉴于Notch在正常和病理中发挥的不同作用 指出，有必要制定 Notch 信号传导和调控的综合机械化学视角 因为需要这样的展望才能全面了解这一关键途径。在这个项目中，我的实验室将 利用我们在化学探针开发和分子工具设计方面的专业知识，以快速解决 有关 Notch 机械转导的重点机械问题。为了区分我们的贡献 与其他人相比，我们将通过结合单分子来追求对该途径的多尺度理解 研究和高分辨率成像，旨在了解受体的激活是如何耦合的 细胞内发生的生物力学事件。特别是新的相关光学和电子显微镜 将被开发并应用于确定Notch信号周围事件的精确时间和位置 转导。此外，为了解决有关来源和规模的重要问题 细胞所经历的外力，我们还将创建Notch的合成版本并将其应用为 基因编码的“张力计”。这项工作的成功执行将为协同作用提供深入的见解 发生在生化和机械线索之间，并增加我们对如何发生的整体理解 细胞感知并解释机械信息。