New Chemical Tools for Exploring Cellular Physiology

摘要 可视化细胞生理学的新化学工具 细胞膜是所有种类的细胞生命所共有的唯一细胞器。离子分布不均 和化学物质穿过质膜导致产生电化学反应， 电位，这种膜电位或电压的快速变化，驱动着细胞的独特生理机能， 神经元和心肌细胞等易兴奋细胞。然而，所有的细胞，即使是非兴奋性细胞，都有一个 膜电位，越来越多的证据支持膜电位在控制 基本的细胞生理学-例如，细胞周期，迁移，增殖和分化-在 非兴奋细胞尽管膜电位在细胞生理学中起着重要作用， 兴奋和非兴奋细胞，我们对这些系统中膜电位的理解仍然存在 不完整，很大程度上是由于缺乏研究细胞生理学的工具， 时间分辨率膜电位的测量依赖于高侵入性、低通量的直接测量。 通过电极（膜片钳）或间接监测下游效应记录电压 通过成像（Ca 2+成像）测量膜电位。我们建议利用有机合成的力量 设计荧光电压传感器以探测神经元中的膜电位动力学的化学， 心肌细胞，除了非兴奋细胞。作为补充，我们正在开发 基于小分子的活性积分器，其随时间积分Ca 2+瞬变以实现高分辨率 在特定的时间窗口期间以长度尺度（超分辨率）重建细胞活动 显微镜、电子显微镜），这些是目前可用的传感器所不能达到的。 虽然我们正在开发的许多工具在神经科学中有应用，但这些策略和 这些技术可以应用于基本的细胞生理学。另外，我的研究项目 重点强调合成化学和分子设计，以实现我们的目标。我预计我们会 揭示了光诱导电子转移、超分子 化学，物理有机化学和生物物理学，因为我们设计和开发这些新工具。

Abstract New Chemical Tools for Visualizing Cellular Physiology The cell membrane is the only organelle shared by all varieties of cellular life. Unequal distribution of ions and chemical species across the plasma membrane results in the generation of an electrochemical potential, and rapid changes in this membrane potential, or voltage, drive the unique physiology of excitable cells like neurons and cardiomyocytes. However, all cells, even non-excitable cells, possess a membrane potential, and mounting evidence supports a role for membrane potential in controlling fundamental cellular physiology—for example, cell cycle, migration, proliferation, and differentiation—in non-excitable cells. Despite the central role of membrane potential to the cellular physiology of both excitable and non-excitable cells, our understanding of membrane potential in these systems remains incomplete, due in large part to a lack of tools for studying cellular physiology with high spatial and temporal resolution. Measurements of membrane potential rely on highly invasive, low throughput direct voltage recording through electrodes (patch clamping) or by indirectly monitoring the down-stream effects of membrane potential via imaging (Ca2+ imaging). We propose to use the power of synthetic organic chemistry to design fluorescent voltage sensors to probe membrane potential dynamics in neurons and cardiomyocytes, in addition to non-excitable cells. In a complementary approach, we are developing small molecule-based activity integrators that integrate Ca2+ transients over time to enable high resolution reconstruction of cellular activity during a specified time window—at length scales (superresolution microscopy, electron microscopy) that are not accessible with currently available sensors. Although many of the tools we are developing have applications in neuroscience, these strategies and techniques can be applied to fundamental cellular physiology. Additionally, my research program places a heavy emphasis on synthetic chemistry and molecular design to achieve our goals. I anticipate we will uncover fundamental insights in areas related to photoinduced electron transfer, supramolecular chemistry, physical organic chemistry, and biophysics as we design and develop these new tools.