Elucidating and Directing Heteromolecular Mechanobiology with Nanoengineered Cell Interfaces

用纳米工程细胞界面阐明和指导异分子力学生物学

• 批准号: 10501851
• 负责人: Haogang Cai
• 金额: $ 40.91万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501851
• 关键词: 3-Dimensional; Address; Adopted; Behavior; Cell physiology; Cell surface; Cells; Cellular biology; Complex; Cues; Custom; Environment; Extracellular Matrix; Fibroblasts; Goals; Growth Factor Receptors; In Vitro; Integrins; Knowledge; Laboratories; Ligands; Mediating; Methodology; Methods; Modeling; Molecular; Nanotechnology; Research; Role; Signal Transduction; Surface; System; T-Cell Receptor; T-Lymphocyte; Technology; base; cellular engineering; in vivo; insight; intercellular communication; mechanotransduction; nanoengineering; novel diagnostics; novel therapeutics; receptor; segregation; single molecule; synthetic biology

PROJECT SUMMARY/ABSTRACT Despite recent progresses in mechanobiology research, there is still a fundamental knowledge gap in critical cellular functions and molecular mechanisms, which take place between the molecular and cellular scale. For systematic, quantitative and deterministic studies, there are key challenges to achieve single-molecule precision, heteromolecular control, simultaneous and independent modulation of multiple physicochemical cues. Based on our unique approach combining top-down nanotechnology and bottom-up synthetic biology, we will overcome these challenges and create “smart” cell interfaces which could probe, sense and manipulate cells and the microenvironment, in an unparalleled precise and controllable manner. The overarching goal of my laboratory is to bring molecular insights into cell biology, and advance the knowledge of cell as a machine, whose behaviors and functions can be predicted and directed. Based on our discoveries in geometric underpinning of molecular mechanobiology, we will address three outstanding questions: (i) What underlies the spatial effects in receptor clustering, and how are they force- mediated? (ii) Are there heteromolecular spatial effects in co-clustering and segregation of different receptors, and what are their roles in signaling crosstalk and integration? (iii) How to use the new knowledge in molecular mechanisms and effectively direct cell functions? Considering the interplay and crosstalk between multiple receptors and physicochemical cues, we will reveal the underlying synergistic mechanisms of heteromolecular mechanobiology for cell-extracellular matrix (ECM) signaling (fibroblast as a model) and cell-cell signaling (T cell as a model). Specifically, for cell-ECM signaling, we will investigate the integrin clustering mechanism, its relationship with cellular contractility, and the crosstalk between growth factor receptors and integrins. For cell- cell juxtacrine signaling, we will investigate the synergistic mechanism of mechanosensing and spatial sensing in T cell receptor clustering and triggering, and the heteromolecular co-clustering mechanism between activatory and inhibitory receptors. Finally, the artificial ECM and artificial cell surfaces we developed in this research will be used to direct critical cell functions for in vitro cell engineering and manufacturing, as well as potential in vivo applications. Overall, our technology will break the limit of mechanobiology study with a single type of bioligands on 2D, rigid, static surfaces, provide heteromolecular control over multiple ligands in a 3D, soft, dynamic fashion, and therefore better mimic the complex in vivo environment. This transformative methodology can be customized and adopted in distinct systems to expand our understanding of fundamental molecular and cellular mechanisms, and apply the new knowledge for novel diagnostic and therapeutic methods.

项目概要/摘要 尽管机械生物学研究最近取得了进展，但关键领域仍然存在基础知识差距 发生在分子和细胞尺度之间的细胞功能和分子机制。为了 系统性、定量性和确定性研究，实现单分子精度面临关键挑战， 异分子控制，同时和独立调节多种物理化学线索。基于 我们独特的方法结合了自上而下的纳米技术和自下而上的合成生物学，我们将克服 这些挑战并创造了“智能”细胞接口，可以探测、感知和操纵细胞和 微环境，以无与伦比的精确和可控的方式。我实验室的总体目标是 将分子洞察带入细胞生物学，并推进细胞作为机器的知识，其行为 并且功能是可以预测和指导的。 基于我们在分子力生物学几何基础方面的发现，我们将解决三个问题 悬而未决的问题：（i）受体聚集的空间效应的基础是什么，以及它们如何迫使- 调解？ (ii) 不同受体的共聚和分离是否存在异分子空间效应， 它们在信号串扰和集成中的作用是什么？ (iii) 如何运用分子生物学的新知识 机制并有效指导细胞功能？考虑多个设备之间的相互作用和串扰 受体和理化线索，我们将揭示异分子的潜在协同机制 细胞-细胞外基质 (ECM) 信号传导（成纤维细胞作为模型）和细胞-细胞信号传导（T 细胞）的力学生物学 作为模型）。具体来说，对于细胞 ECM 信号传导，我们将研究整合素聚类机制及其 与细胞收缩力的关系，以及生长因子受体和整合素之间的串扰。对于细胞- 细胞近分泌信号传导，我们将研究机械传感和空间传感的协同机制 T细胞受体聚集和触发，以及激活剂之间的异分子共聚集机制 和抑制性受体。最后，我们在本研究中开发的人工 ECM 和人工细胞表面将 用于指导体外细胞工程和制造的关键细胞功能以及潜在的体内细胞功能 应用程序。 总体而言，我们的技术将突破单一类型生物配体在二维、刚性、 静态表面，以 3D、柔软、动态的方式提供对多个配体的异分子控制，以及 因此更好地模拟复杂的体内环境。这种变革性的方法可以定制 并在不同的系统中采用，以扩展我们对基本分子和细胞机制的理解， 并将新知识应用于新的诊断和治疗方法。