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.

项目摘要/摘要 尽管机制研究最近取得了进展，但关键仍然存在基本知识差距 细胞功能和分子机制，发生在分子和细胞尺度之间。为了 系统的，定量和确定性研究，要实现单分子精度存在关键挑战， 杂分子控制，对多种物理化学提示的简单和独立调节。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 这些挑战并创建“智能”细胞界面，可以探测，感官和操纵细胞以及 微环境，以无与伦比的精度和可控的方式。我实验室的总体目标是 将分子见解带入细胞生物学，并推进细胞的知识，作为机器的行为 可以预测和定向功能。 根据我们在分子机械生物学的几何基础上发现的发现，我们将解决三个 出色的问题：（i）是什么基于受体聚类的空间效应的基础，它们如何强制 介导？ （ii）在不同接收器的共聚类和隔离中是否存在异构分子空间效应， 他们在信号串扰和集成中的作用是什么？ （iii）如何在分子中使用新知识 机制并有效地导致细胞功能？考虑多个的相互作用和串扰 受体和物理线索，我们将揭示异构分子的潜在协同机制 细胞 - 细胞基质（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）的机械生物学 作为模型）。特别是对于细胞ECM信号，我们将研究整联蛋白聚类机制，即它 与细胞收缩力以及生长因子受体和整合素之间的串扰关系。用于细胞 - 细胞并折信号传导，我们将研究机械传感和空间感测的协同机制 在T细胞受体聚类和触发中，以及激活之间的异构共聚类机制 和抑制受体。最后，我们在这项研究中开发的人造ECM和人造细胞表面将会 用于指导体外细胞工程和制造的关键细胞功能，并在体内潜在 申请。 总体而言，我们的技术将用2D，刚性，刚性，刚性，刚性，刚性的一种类型的生物体来打破机械生物学研究的极限 静态表面，以3D，柔软，动态的方式对多种配体提供异余分子控制，并且 因此，更好地模仿体内环境。可以定制这种变革性方法 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颖的诊断和治疗方法。