Research
All cells studied to date, from Archaea to neurons, synthesize complex glycans and use them to form a peripheral structure (the glycocalyx) that is their first point of contact with the outside world. All multicellular systems produce and dynamically regulate glycosylated extracellular matrices (ECM) that perform functions ranging from mechanical sensing/actuation to immunological regulation.
Extracellular biomolecules form an interconnected, organism-wide network, which is collectively termed the extracellular matrix. These secreted and membrane-associated biomolecules have unique features that present both challenges and opportunities to biotechnologists.
As cell and molecular biology progress from cultured monolayers to tissues, the glycocalyx and ECM will need to be integrated into conceptual frameworks and therapeutic strategies. Extracellular biology, however, has lagged behind its intracellular counterpart, due largely to challenges which arise from core properties of extracellular biomolecules: they are not protected by plasma membranes and they are densely glycosylated. They are therefore difficult to manipulate with genetics and resistant to characterization through sequencing approaches. At the same time, those core properties present us with opportunities to develop technologies and therapeutics for modulation of biological systems.
Current projects center on small molecule fluorescent probes for live structural imaging, biosensor design for functional imaging, glycan-directed methods for electron microscopy (EM), and cryo-EM approaches for characterization of extracellular assemblies. Our aim is to uncover principles by which extracellular structures and events govern biochemical and mechanical signaling in complex tissues, and to use that knowledge to improve human health.
Transmission electron micrograph of the glycocalyx (G) of a mouse capillary, stained with lanthanum nitrate.
2-photon fluoroscence microscopy volume of live mouse tissue, with fibers of the extracellular matrix labeled using Rhobo6.