Research | Shi Lab

Research Interests

To elucidate how cells drive developmental mechanisms across all scales, we leverage super-resolution microscopy and chemical synthesis to develop novel cutting-edge imaging and multiomics methods and apply these methods to study the following specific topics:

1 minute about Shi Lab

I. How cellular machineries are organized at the molecular scale?

Seeing is believing. A major objective of our research program is to directly visualize how cells organize proteins, RNA, and DNA in space and time. We have developed a series of super-resolution microscopy methods to dissect the architecture of cellular structures at molecular resolution and with high labeling efficiency, brightness, and detection sensitivity. We are particularly interested in the structure-function relationships of the nuclear lamina, chromatin, cytoplasmic vesicles, and cellular protrusions called cilia.

Methods: Expansion Microscopy (ExM), Stochastic Optical Reconstruction Microscopy (STORM), Structured Illumination Microscopy (SIM), Airyscan Microscopy

II. How single-cell multiomic data are organized at the spatial scale?

Over the last few years, we are witnessing rapid advances in the fields of single-cell transcriptomics, genomics, and proteomics. However, most tissues and organs are solid, with cells encased within a complex extracellular matrix network. Studying single cells from solid tissues usually requires their mechanical and enzymatic disaggregation. As a result, the positional information is lost, which is otherwise essential for a proper understanding of how cells cooperate in tissues. We take optical and chemical approaches to develop novel, spatially-resolved multiomic methods, which isolate cells without homogenization, enable cell phenotyping with super-resolution, and allow multiomics in the same single cells. This novel platform will significantly advance our knowledge of how cell phenotypes are maintained in native tissue and become perturbed in disease.

III. How do primary cilia mediate Hedgehog signaling?

The hedgehog signaling pathway is the key signaling regulator of embryonic tissue patterning and adult tissue homeostasis. Defects in Hedgehog signaling can cause a multitude of developmental diseases, such as congenital heart disease, and cancers, such as melanoma. Primary cilia, specialized protrusions on cell membranes, have an essential role in Hedgehog signaling in mammals. Our research objective is to determine the molecular mechanisms that underlie the regulation of Hedgehog signaling by primary cilia. Empowered by fast imaging and endogenous labeling technologies, we are able to directly watch and analyze the behavior of signaling and transporter molecules in action.

Methods: Live-cell single-particle tracking, Light-sheet microscopy, Total Internal Reflection Fluorescence Microscopy (TIRF), photoconversion