CAREER: A Chemical Technology to Define Target-Specific Bioreactivity: Integrating Research and Education at the Crossroads of Chemistry and Biology

细胞的内部工作需要对一系列单独的化学事件进行精致的协调。各种“仪器”通过大量的信号相互交流，这些信号是传递细胞状态信息的分子。对于细胞的正常功能，信号传递的时机决定了一切。为了了解活细胞内发生的事情，研究人员常规地将信号分子应用于细胞，并观察发生了什么。这种方法有严重的局限性，因为整个细胞都暴露在信号中，随着化合物进入体内，时间在很大程度上会丢失。这些影响可能会导致意想不到的后果，这些后果可能无法解决。该提案旨在克服这些限制，并获得对特定信号分子释放的确切位置和时间的控制。研究人员通过开发一套新的化学工具来满足这一迫切需求，利用这些工具，反应信号可以在准确的时间选择性地传递给细胞中的特定蛋白质。这样的研究突破将提供关于生物学中至关重要的化学定向信号处理机制的时间分辨信息。这项研究使实验室的研究生获得了良好的技术开发基础，将化学和生物结合在一起。综合推广的目标是突出现代交叉化学生物学的概念和工具，特别是针对K-12教育工作者和来自代表性不足人群的学生。通过这个奖项，化学系的生命过程化学计划资助来自康奈尔大学的助理教授伊蒙·艾伊以时空精度评估基本的蛋白质/小分子信号相互作用。由生物活性信号转导的亲电体诱导的非酶翻译后蛋白质修饰，如脂质衍生的醛，已经出现在氧化还原连接的细胞信号转导中发挥重要作用。这项建议避免了传统的全细胞治疗方法，引入了一种新的化学驱动方法，通过在其他天然/健康细胞中的精确时间用一个诱导剂选择性地对一个靶点进行化学扰动来询问这些相互作用。来自PI实验室的最新数据表明，她的新的定向修饰策略能够定量评估活细胞中单个非酶辅助蛋白质修饰事件的靶标和电泳体特定的时间动态。生理上相关的反应性和特异性的知识将使人们能够预测给定的反应性小分子信号在细胞决策中如何在目标的微环境中发挥作用。

The inner workings of cells require exquisite orchestration of an array of individual chemical events. The various "instruments" communicate with one another through numerous signals, molecules that convey information about the state of the cell. For the proper function of cells, the timing of signaling is everything. In order to understand what is going on inside live cells, researchers routinely apply the signaling molecules to cells and observe what happens. There are serious limitations to this approach because the entire cell is exposed to the signal and timing is largely lost as the compounds find their way inside. These effects can lead to unintended consequences that can be impossible to sort out. The proposal aims to overcome these limitations, and to gain control over the exact location and timing of release of specific signaling molecules. The investigator addresses this pressing need by developing a set of new chemical tools with which reactive signals can be selectively delivered to specific proteins in cells at a precise time. Such a research breakthrough will provide time-resolved information on the chemically directed signal-processing mechanisms of fundamental importance in biology. The research enables graduate students in the lab to acquire excellent grounding in technological development interfacing chemistry and biology. The integrated outreach goal is to highlight modern crosscutting chemical biology concepts and tools, specifically aimed at K-12 educators and students from underrepresented populations.With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Assistant Professor Yimon Aye from Cornell University to evaluate with spatiotemporal precision the fundamental protein/small-molecule signal interactions. The non-enzymatic post-translational protein modifications inducible by the bioactive signaling electrophiles, such as lipid-derived aldehydes, have emerged to play major roles in redox-linked cell signaling. Avoiding the conventional whole-cell treatment approaches, this proposal introduces a new chemistry-driven approach to interrogate these interactions by selective chemical perturbation of one target with one inducer at a precise time in an otherwise native/healthy cell. The most recent data from the PI's lab suggest that her new directed modification strategy enables quantitative assessment of target- and electrophile-specific temporal dynamics of individual non-enzyme-assisted protein modification events in living cells. The knowledge of physiologically relevant reactivity and specificity will enable the prediction of how a given reactive small-molecule signal may function within microenvironments of a target in cellular decision-making.