NIH Director's Pioneer Award

纳米结构因其在电子学、光子学和电子学等领域的应用前景而受到广泛关注。 信息存储。我相信这些微小的结构也具有推动生物医学发展的巨大潜力 研究。特别是，我一直想利用纳米结构的力量从根本上改变 细胞的行为是被探测和调控的。在这里，我建议开发下一代工具集，用于研究和 通过结合三类互补的纳米结构来操纵细胞活性：金纳米笼 能够吸收近红外光并有效地将其转化为热；能够改变的智能聚合物 对温度的微小变化作出反应的构象；以及酶。刺激响应性聚合物将是 共价连接到酶活性部位附近的特定位置；生成的单位将结合在一起 到金纳米笼的表面。当纳米笼被脉冲激光击打时，聚合物构象将 快速、可逆地在伸展和折叠状态之间切换，打开和关闭酶。至 证明了这种混合纳米结构的生物学重要性，我将首先将它们应用于操纵细胞 如细胞凋亡等行为。各种诱捕技术也将被采用来控制 单个细胞内外的杂合纳米结构。我将第一次能够确定 启动细胞凋亡所需的最低活性酶的数量，以及是否以及如何在空间上定位 酶影响细胞凋亡信号转导。一旦它被证明是用于细胞凋亡，这个概念将被扩展到 开发类似的杂交纳米结构，用于读取和控制其他细胞过程和信号通路。 这种基于空间和时间可寻址纳米结构的工具包与许多其他工具相辅相成 生物成像技术正在开发中，并将在研究复杂的生物系统中得到广泛应用。

Nanostructures have received extensive attention for their promising applications in electronics, photonics, and information storage. I believe these minuscule structures also hold great potential for advancing biomedical research. In particular, I have always wanted to harness the power of nanostructures to radically change the way cell behavior is probed and regulated. Here I propose to develop the next generation of toolset for studying and manipulating cell activity by bringing together three classes of complementary nanostructures: gold nanocages capable of absorbing near infrared light and effectively converting it to heat; smart polymers capable of changing conformation in response to small variation in temperature; and enzymes. The stimuli-responsive polymer will be covalently attached to a specific position near the active site of the enzyme; the resultant unit will be conjugated to the surface of gold nanocage. When the nanocage is struck with a pulsed laser, the polymer conformation will be quickly and reversibly switched between the extended and collapsed states, turning on and off the enzyme. To demonstrate the biological importance of such hybrid nanostructures, I will initially apply them to manipulate cell behavior such as apoptosis. A variety of trapping techniques will also be adapted to control the spatial position of the hybrid nanostructure inside and outside an individual cell. For the first time, I will be able to ascertain the minimum number of active enzymes required to initiate apoptosis, and whether and how the spatial location of the enzyme affects apoptosis signaling. Once it has been demonstrated for apoptosis, the concept will be extended to develop similar hybrid nanostructures for reading and controlling other cellular processes and signaling pathways. Such a toolset based on spatially and temporally addressable nanostructures is complementary to many other bioimaging techniques under development, and will find broad use in studying complex biological systems.