Ion transport across the hydrophobic barrier of the cell membrane is a primary challenge faced by all cells. Such transport sets up and exploits ion gradients, thus providing the basic energy and signaling events that are the foundation of life. It is fascinating to study the molecular mechanisms of the proteins that catalyze this transport.

A major research focus in the lab is on the chloride-selective CLC family, which contains both types ion-transport protein, channels and transporters. CLC proteins are expressed ubiquitously and perform diverse physiological functions in cardiovascular, neuronal, muscular, and epithelial tissue. Our lab uses a combination of biophysical methods to investigate membrane-protein structure and dynamics together with electrophysiological analyses to directly measure function to determine the molecular mechanisms of these proteins.

We also apply our expertise on ion-transport mechanisms to interdisciplinary collaborations. In a longstanding collaboration with Professor Justin Du Bois (Chemistry), we are developing and employing novel chemical tools for studying chloride channels. Most recently, the Du Bois and Maduke laboratories have teamed up with Profs John Huguenard (Neurology) and Ron Dror (Computer Science) to study CLC-2 channels. In the brain, the roles of voltage-gated sodium-, potassium-, and calcium-selective ion channels are well established. In contrast, the specific functions of the voltage gated chloride-selective channel CLC-2, which is expressed throughout the brain, have been much less studied and are not sufficiently understood. We are developing novel tools and approaches for studying CLC-2.

In another multi-disciplinary collaboration, lab members are collaborating with researchers in Radiology (Butts Pauly lab), Electrical Engineering (Khuri-Yakub lab), Neurobiology (Baccus lab), and Molecular & Cellular Physiology (Goodman and Madison labs) to investigate the mechanism of ultrasound neuromodulation. Ultrasound neuromodulation is a rapidly emerging and revolutionary field. Because ultrasound can modulate neural activity non-invasively with high spatial resolution anywhere in the brain, it has tremendous potential. The revolutionary implications include a noninvasive experimental approach to perturb and study specific brain structures, as well as treatments for Parkinson’s disease, epilepsy, Alzheimer’s, stroke, and many other brain diseases. However, significant barriers remain between this vision and its realization, as we lack a mechanistic understanding of US’s effects on neural activity. By integrating ultrasound neuromodulation studies at the molecular, cellular, circuit, and whole-animal level, we aim to overcome this challenge.