Research
All multicellular systems studied to date, from bacterial colonies to vertebrate brains, deposit molecular assemblies in the spaces between their cells. This extracellular matrix (ECM) is essential to nearly every process that involves cellular cooperation, from mechanical actuation to immunological defense.
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 molecular and cell biology continue to progress from cultured monolayers to tissues, the ECM will need to be incorporated into conceptual frameworks and therapeutic strategies. Extracellular biology, however, has lagged behind its intracellular counterpart, due largely to challenges which arise from two core properties of extracellular biomolecules: they are not protected by cell membranes and they are densely glycosylated. Those core properties render ECM biomolecules resistant to conventional genetics- and sequencing-based methods of interrogation.
Our lab takes the view that chemical biology and advanced imaging are poised to dramatically accelerate the study of ECM physiology and pathology. 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 cryoEM approaches for characterization of disease-driving extracellular assemblies. Our aim is to uncover principles by which ECM drives biochemical and biophysical signaling in mammalian tissues, to develop therapies that take advantage of the unique and underexplored chemical space of extracellular molecules, and to widely distribute methods that will allow others to join those long-term efforts.
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.