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Welcome to the Zhou Lab!

To elucidate fundamental mechanisms of cellular functions and diseases, we must understand the spatial and temporal organization of multi-protein assemblies and their interactions with other cellular components at the molecule level. Neuronal chemical synapses are typical examples of such nanoscale structures. Efficient synaptic transmission depends on the trans-cellular alignment and high-order organization of nanoscale supramolecular assemblies spanning the synaptic cleft. The nanoscale, activity-dependent reorganization of key synaptic proteins, including neurotransmitter receptors, is widely known as a mechanism of synaptic plasticity. Synaptic plasticity is essential for perception, decision making, learning, and memory formation. Additionally, major components of these synaptic protein assemblies are associated with neurodevelopmental disorders and other mental illnesses. Our long-term goal is to address foundational questions on synaptic transmission and plasticity using the emerging framework of macromolecular assemblies, thereby contributing to the development of pharmacological therapeutics for neurodevelopmental disorders.

Currently, cell imaging techniques like confocal and super-resolution microscopy are employed to visualize the behavior of specifically labeled proteins within their native biological contexts, achieving resolutions down to 10 nm. Recently, cryo-electron tomography (cryo-ET) has emerged as a powerful technique capable of producing unaveraged high-resolution (2-4 nm) 3D volume reconstructions (tomograms) of macromolecular and subcellular biological structures inside cells in near-native, frozen-hydrated states. These 3D cryo-tomograms provide invaluable insights into molecular organization within cells, but precisely identifying proteins or structures within these tomograms remains a challenge. Moreover, challenges persist in bridging the resolution gap and correlating data between light microscopy (LM) and electron microscopy (EM). To advance molecular-resolution cell imaging, we will develop and use genetically encoded universal protein tags that are simultaneously visible by both LM and EM. These tags will be capable of being targeted to intracellular proteins of interest with pinpoint precision and unambiguous identification (better than 1 nm) in the near-native cellular state. Our innovative work in LM/EM dual-visible labeling promises to revolutionize the visualization of proteins within cells at the molecular level. The potential impact of this research spans a wide range of biomedical inquiries, driving scientific discovery and innovation in cellular biology.