Our fundamental interest is in how ion channels enable intercellular communication. Our principal tools for investigating this are  cryo-electron microscopy (cryo-EM), cryo-electron tomography (cryo-ET), and electrophysiology.

Ionotropic Glutamate Receptors (iGluRs)

iGluRs are ligand-gated ion channels that enable communication between neurons in the nervous system by receiving chemical neurotransmitters (e.g., glutamate) from neurons at synapses and enabling cation influx into the post-synaptic neuron. We are interested in how the range of iGluR subtypes accommodate this process throughout different brain regions, and how this process is regulated and tuned to accommodate the needs of specific circuits and cell types. We are also interested in how mutations and dysregulation of iGluRs in neurological and neurodevelopmental diseases alter iGluR function. Our ultimate goal is to use our results to build precision therapeutics against iGluRs in disease.

Tight Junctions

While TARP teraspanins regulate iGluR function in the brain, they are structurally identical to another class of tetraspanins, claudins, that form tight junctions. What are the tetraspanin moieties that enable tight junction function (e.g., tissue barrier formation) vs TARP function (e.g., tuning neurotransmitter responses via iGluR regulation)?

Across all epithelial and endothelial tissues, tight junctions are paracellular gatekeepers that regulate tissue homeostasis and cell polarity as the most-apical cell-cell complex. Dysregulation of tight junctions can lead to cancers, neurodegeneration, visual impairment, gastrointestinal distress, and breathing impairment. Dysregulation or hijacking of tight junction components also plays a major role in viral entry, such as with Hepatitis C, Zika, and SARS-CoV-2. In addition, understanding tight junctions at the blood brain barrier is critical for improving CNS drug delivery. Despite the critical role that tight junctions play in physiology and disease, we lack a precise molecular and atomic understanding of how they function, how they assemble, as well as their architecture. This is a fundamental barrier in understanding the major barrier forming complex in tissues, and in drug design. We are using molecular modeling, cryo-EM, cryo-ET, single molecule biophysics, and cell biology to understand tight junctions.

Time-Resolved Cryo-EM

We are interested in developing time-resolved cryo-EM and cryo-ET to understand the atomistic details of how proteins work as a function of time. Despite the power of cryo-EM to elucidate the structural details of proteins and protein complexes, the temporal resolution of traditional specimen preparation is orders of magnitude slower than the pace at which life occurs. We are building cryo-EM specimen preparation devices that will allow us, and others, to capture biological processes at a physiologically relevant timescale.