Spatial and topological control of receptor signaling using DNA nanotechnology

使用 DNA 纳米技术对受体信号传导进行空间和拓扑控制

• 批准号: RGPIN-2020-05966
• 负责人: Chou, Leo
• 金额: $ 2.11万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746042
• 关键词: Spatial; topological; control; receptor; signaling

The Chou group's research program explores design principles of self-assembling nanoscale devices. We currently focus on developing DNA as a medium for 3D nanofabrication, and on functionalizing engineered DNA nanostructures with lipids, polymers, proteins to interface them with biological systems. These DNA-scaffolded nanostructures are unique among synthetic nanomaterials in that their properties are sequence-programmable, which enables exquisite control over their structure and dynamics. Our group is using these capabilities to construct nanodevices that interface with cell membrane receptors for manipulating cell signaling pathways. Of particular interest to us are signaling pathways triggered through large-scale contacts, such as cell-cell and cell-pathogen interactions. These interactions induce cell activation states distinct from those induced using soluble ligands, but are especially difficult to recapitulate synthetically because they involve hetero-multivalent receptor-ligand interactions as well as their drastic spatial re-organization on the plasma membrane. Leveraging the programmability of DNA nanotechnology, this NSERC proposal aims to build an artificial cell membrane capable of spatial control over such multivalent receptor-ligand interactions. The specific aims are to: (1) establish the methodology of manufacturing an artificial cell membrane by combining DNA nanostructures with lipids, polymers, proteins, and microspheres; (2) understand how biological fluids, such as serum, influence features of the artificial cell membrane; (3) assess ability of the artificial cell membrane to toggle cell signaling as a function of its design features; (4) demonstrate ability to potentiate cell signaling via display of hetero-multivalent ligand arrays on the artificial cell membrane. The outcome will advance knowledge of cell signaling biology, generate a programmable cell-interfacing material for use by the biophysics, synthetic biology, and biomedical engineering community, and lead to next-generation technologies for cell manufacturing and for directing cell fate ex vivo and in vivo.

周团队的研究项目探索了自组装纳米设备的设计原理。我们目前专注于开发DNA作为3D纳米制造的媒介，并利用脂质、聚合物和蛋白质使工程DNA纳米结构功能化，使其与生物系统接口。这些以DNA为支架的纳米结构在合成纳米材料中是独一无二的，因为它们的性质是序列可编程的，这使得能够精确地控制它们的结构和动力学。我们的团队正在利用这些能力来构建与细胞膜受体接口的纳米设备，以操纵细胞信号通路。我们特别感兴趣的是通过大规模接触触发的信号通路，例如细胞与细胞和细胞与病原体的相互作用。这些相互作用诱导的细胞激活状态不同于使用可溶性配体诱导的激活状态，但尤其难以综合概括，因为它们涉及异质多价受体-配体相互作用以及它们在质膜上的剧烈空间重组。利用DNA纳米技术的可编程性，NSERC的这项提议旨在建立一种人造细胞膜，能够对这种多价受体-配体相互作用进行空间控制。其具体目标是：(1)建立通过将DNA纳米结构与脂质、聚合物、蛋白质和微球相结合来制造人造细胞膜的方法；(2)了解生物流体，如血清，如何影响人造细胞膜的特征；(3)评估人造细胞膜根据其设计特征触发细胞信号的能力；(4)通过在人造细胞膜上展示异种多价配体阵列来展示增强细胞信号传递的能力。这一成果将促进对细胞信号生物学的了解，产生一种可编程的细胞接口材料，供生物物理学、合成生物学和生物医学工程界使用，并导致下一代细胞制造技术和指导体外和体内细胞命运的技术。