Nanomodules for interrogating chemical, spatial, and mechanical dynamics of cell surface receptors

用于研究细胞表面受体的化学、空间和机械动力学的纳米模块

• 批准号: 9427924
• 负责人: Young-wook Jun
• 金额: $ 31.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9427924
• 关键词: Address; Adherens Junction; Area; Atomic Force Microscopy; Behavior; Biochemical; Biological Neural Networks; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Cellular biology; Chemicals; Chemistry; Complex; Coupled; Cues; Defect; Development; Developmental Process; Diagnosis; Disease; E-Cadherin; Event; Excitatory Synapse; Explosion; Extracellular Matrix; Focal Adhesions; Future; Generations; Goals; Heterogeneity; Image; Imaging technology; Immune System Diseases; In Vitro; Individual; Inhibitory Synapse; Integrins; Intercellular Junctions; Investigation; Label; Ligand Binding; Ligands; Logic; Magnetism; Malignant Neoplasms; Mechanical Stimulation; Mechanics; Membrane; Methodology; Methods; Morphologic artifacts; Nanotechnology; Neoplasm Metastasis; Organism; Pathologic Processes; Physiological Processes; Process; Proteins; Receptor Signaling; Regulation; Research; Resolution; Role; Signal Transduction; Signaling Protein; Specificity; Synapses; System; Technology; Therapeutic; Time; base; biological systems; crosslink; fluorescence imaging; imaging modality; improved; innovation; insight; interest; mechanical force; mechanical load; mechanical properties; nanoparticle; nanoprobe; nanotool; notch protein; optogenetics; outcome forecast; programs; receptor; relating to nervous system; response; segregation; single molecule; spatiotemporal; stem; synaptic function; targeted imaging; temporal measurement; tool; usability

ABSTRACT The ability to manipulate cellular activities through targeted and precise perturbation promises to dramatically enhance our understanding of biological systems from single molecules to systems-level cell biology. Contrary to the recent explosion of optogenetic modules for electro and chemical signal control, no perturbative tools allowing precise spatiotemporal control of mechanosignaling have been presented so far, despite the importance of mechanosignaling in many developmental, physiological, and pathological processes. The challenge of developing a perturbation toolkit for mechanosignaling stems from the fact that many mechanically-activated processes are localized in space and time and additionally require mechanical loading to become fully activated. To address this, we propose to develop an advanced nanoprobe system with integrated targeting, imaging, and force-generating components. By taking advantage of such multifunctional nanoprobe capabilities, we will systematically investigate the differential effects of biochemical interaction at cell surface, spatial receptor segregation, and mechanical stimulation on regulation of mechanosignaling processes and cellular responses. As initial studies, we propose to investigate interaction and signaling dynamics of neuroligin, integrin, and E-cadherin, key signaling proteins in synaptic function, cell-matrix interactions, and cell-cell junctions, respectively. Ultimately, we aim to provide a platform technology for the systematic investigation of operating principles for a wide range of mechanosensitive proteins, accelerating our understanding of mechanosignaling mechanisms and regulation.

抽象的 通过有针对性和精确的扰动来操纵细胞活动的能力有望显着 增强我们对生物系统从单分子到系统级细胞生物学的理解。相反 对于最近用于电化学信号控制的光遗传学模块的爆炸式增长，没有微扰工具 迄今为止，已经提出了允许精确时空控制机械信号的方法，尽管 机械信号在许多发育、生理和病理过程中的重要性。这 开发机械信号扰动工具包的挑战源于以下事实： 机械激活的过程在空间和时间上是局部的，并且还需要机械加载 变得完全激活。为了解决这个问题，我们建议开发一种先进的纳米探针系统 集成瞄准、成像和力生成组件。通过利用这种多功能 纳米探针的能力，我们将系统地研究生化相互作用的不同影响 细胞表面、空间受体分离和机械刺激对机械信号调节的影响 过程和细胞反应。作为初步研究，我们建议研究相互作用和信号传导 Neuroligin、整合素和 E-钙粘蛋白、突触功能中的关键信号蛋白、细胞基质的动力学 分别是相互作用和细胞-细胞连接。最终，我们的目标是提供一个平台技术 对各种机械敏感蛋白质的操作原理进行系统研究，加速我们的研究 了解机械信号机制和调节。