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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 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. To better understand CLC-2 function and mechanisms, we collaborate with Professors Justin Du Bois (Chemistry), Ron Dror (Computer Science) and John Huguenard (Neurology) to develop and employ novel chemical tools.
In the kidney, CLC-Ka and CLC-Kb channels play essential roles in maintaining salt and water balance, which is critical to overall health. We hypothesize that CLC-Ka is a potential drug target for treating pathologic water retention (hyponatremia), which frequently complicates the management of patients with hypertension, heart failure, or cirrhosis. To test this hypothesis, we are collaborating with Drs. Wah Chiu (Bioengineering), Mark Smith (Medicinal Chemistry Knowledge Center), Ron Dror (Computer Science) and Alan Pao (Medicine). Using a structure-based approach, we are developing small-molecule inhibitors that are selective and potent inhibitors of CLC-Ka. Together with a medicinal chemistry approach to that optimize pharmacokinetic properties, we will develop and then use these inhibitors to test in vivo efficacy.
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.