CAREER: New Reporters for Temporally-Gated Integration of Neuronal Activity

在化学系生命过程化学项目的支持下，密歇根大学的Wenjing Wang将开发新的分子工具来研究大脑信号特异性神经元群体。功能性神经元群体在特定行为期间被激活，是我们认知功能和行为的基础。它们通常稀疏地分散在其他看似相同的神经元中，因此，对于进一步的研究来说是具有挑战性的。目前，仍然需要报告者在检测到神经元活动后几分钟内用读数标记这些功能性神经元。为满足这一需求而提出的项目对分子生物学和神经科学具有广泛的潜在影响。此外，拟议的研究将为研究生和本科生提供培训机会，以获得分子生物学和蛋白质工程技术的知识和先进技能。该项目产生的前沿研究成果将被纳入研究生课程材料，并与密歇根大学自然历史博物馆合作，与公众进行科学交流。该项目旨在开发一类新的报告分子，用于标记在特定行为期间激活的神经元群体。记者快速回答的能力依赖于神经元活动引起的化学变化对酶的快速激活。定向进化和合理的蛋白质设计方法将首先应用于细胞培养中的报告基因的开发和优化，然后应用于动物模型。优化的方法将允许通过在检测到信号事件后立即标记神经元来研究动物模型中的神经元活性。新的报告者有可能促进对行为背后的神经元活动和电路的询问。建议的方法，如果成功的话，预计将有广泛的科学影响，因为他们可以，在原则上，被应用到广泛的生物过程，涉及蛋白质-蛋白质interactions.This奖项的研究反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

With the support of the Chemistry of Life Processes Program in the Chemistry Division, Wenjing Wang of the University of Michigan will develop new molecular tools to study brain signaling-specific neuronal populations. Functional neuronal populations, activated during specific behaviors, underlie our cognitive functions and behaviors. They are usually sparsely scattered among other seemingly identical neurons, and, therefore, are challenging to access for further study. Currently, there is still a need for reporters to label these functional neurons with readout within minutes after detecting the neuronal activity. The proposed project to address this need has broad potential impact on molecular biology and neuroscience. Additionally, the proposed research will provide graduate and undergraduate students training opportunities to acquire knowledge of and advanced skills in molecular biology and protein engineering techniques. Frontline research results generated from this project will be incorporated into graduate level course materials and, in collaboration with the Museum of Natural History at the University of Michigan, in science communication with the public. This project seeks to develop a new class of reporters for labeling neuronal populations activated during specific behaviors. The reporters’ ability to answer quickly relies on the fast activation of an enzyme by chemical changes caused by neuronal activity. Directed evolution and rational protein design methods will be applied to the development and optimization of the reporters in cell cultures first and then in animal models. The optimized methods would allow the study of neuronal activity in animal models by immediate labeling of neurons upon detection of the signaling events. The new reporters have the potential to facilitate the interrogation of neuronal activity and circuits that underlie behaviors. The proposed methods, if successful, are expected to have broad scientific impact as they could, in principle, be applied to the study of a wide range of biological processes that involve protein-protein interactions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.