CAREER: Advancing Proximity Labeling Mass Spectrometry to Characterize Neuronal Mitochondrial Dynamics

在化学系生命过程化学项目的支持下，来自华盛顿大学的乔治的凌浩正在开发新的生物分析化学方法来研究人类神经元中的线粒体动力学。线粒体是细胞的发电站;它们产生ATP并作为许多代谢途径的枢纽。大脑中的神经元严重依赖于线粒体功能，因为需要极高的能量来支持突触活动。然而，神经元线粒体的特定分子微环境尚未完全了解，部分原因是技术限制。该项目将开发基于质谱（MS）的技术，以表征人类干细胞衍生神经元中分子水平上的动态线粒体活动和相互作用。通过与当地化学仪器公司和MS讨论组的合作，将组织一个夏季MS研讨会，汇集来自不同层次的学生以及来自当地学术，工业和政府机构的科学家。将整合一系列研究、教育和外联活动，以加强大学和地区一级的学生学习和培训经验，并促进STEM（科学、技术、工程和数学）的可及性和多样性。拟议的研究旨在解决主要的技术挑战和知识差距，使用质谱（MS）技术研究人类神经元中的分子网络和亚细胞微环境。尽管在理解线粒体功能方面取得了进展，但捕获动态线粒体微环境在技术上具有挑战性，特别是在具有高度极化结构的神经元中。将开发一组基于MS的邻近标记策略来研究人诱导多能干细胞（iPSC）衍生的神经元中的线粒体活性、功能、代谢调节和膜动力学。 该研究计划将提供广泛适用的化学工具来研究亚细胞生物微环境，并为线粒体动力学和神经生物学提供新的见解。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes program in the Division of Chemistry, Ling Hao from George Washington University is developing novel bioanalytical chemistry methods to study mitochondrial dynamics in human neurons. Mitochondria are the powerhouses of the cell; they produce ATP and function as hubs for many metabolic pathways. Neurons in the brain rely heavily on mitochondrial functions because have extremely high energy demands to support synaptic activities. However, the specific molecular microenvironment of neuronal mitochondria is not fully understood, partly due to technological limitations. This project will develop mass spectrometry (MS)-based techniques to characterize the dynamic mitochondrial activities and interactions at the molecular level in human, stem cell-derived neurons. Through partnership with local chemistry instrument companies and MS discussion group, a summer MS workshop will be organized to bring together students from different levels as well as scientists from local academic, industry, and government institutions. A set of research, education and outreach activities will be integrated to enhance student learning and training experiences at the university and regional levels and to promote accessibility and diversity in STEM (science, technology, engineering and mathematics). The proposed research aims to address major technical challenges and knowledge gaps to study molecular networks and the subcellular microenvironment in human neurons using mass spectrometry (MS) techniques. Despite the advancements in understanding mitochondrial functions, it is technically challenging to capture the dynamic mitochondrial microenvironment, particularly in neurons with highly polarized structures. A set of MS-based proximity labeling strategies will be developed to study mitochondrial activities, functions, metabolic regulations, and membrane dynamics in human induced pluripotent stem cells (iPSCs)-derived neurons. This research program will provide widely applicable chemistry tools to study sub-cellular biological microenvironment as well as provide new insights into mitochondrial dynamics and neurobiology.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.