Our Research

My research interests and expertise encompass neuroscience, protein structure, computational biology, and evolution. Main focus of my research group is on structure and function studies of voltage-gated ion channels, computational design and chemical synthesis of subtype-specific modulators of voltage-gated ion channels, development of computational methods for membrane protein structure prediction and design, and analysis of evolution of human voltage-gated ion channels. Function and modulation of neuronal sodium channels are critical for the neuromodulation of electrical excitability and synaptic transmission in neurons - the basis for many aspects of signal transduction, learning, memory and physiological regulation. Mutations in neuronal voltage-gated sodium channel genes are responsible for various human neurological disorders. Furthermore, human neuronal voltage-gated sodium channels are primary targets of therapeutic drugs used as local anesthetics and for treatment of neurological and cardiac disorders. My first project is focusing on studying of neuronal voltage-gated sodium channels structure, function, and modulation in order to design new therapeutically useful drugs for treatment of pain and epilepsy. Serious, chronic pain affects at least 116 million Americans each year and epilepsy affects nearly 3 million Americans and 50 million people Worldwide. However, the treatment of chronic pain and epilepsy remains a major unmet medical need because the use of currently available drugs is limited due to incomplete efficacy and/or significant side effects. Considerable efforts by pharmaceutical industry toward identifying selective inhibitors of one or more of Nav channel subtypes did not generate any genuinely subtype selective blockers and none are currently advancing through clinical trials. My laboratory uses an innovative approach to design novel subtype selective Nav channel blocking drugs with high efficacy and minimum side effects. Novel drugs will be tested using methods of electrophysiology, biochemistry, and molecular biology. This project will provide key structural information on the molecular basis of neuronal voltage-gated sodium channels function and its interaction with therapeutically useful subtype-specific modulators. Understanding of function and modulation of the neuronal voltage-gated sodium channels on structural level will give us profound insights into the fundamental mechanisms underlying neuromodulation and signal transduction.

Reprogramming Neuronal Electrical Signaling with Targeted Ion Channel Modulation

Ion channel proteins are key regulators of electrical signals in cells, controlling neuronal communication and physiological functions as diverse as hormone secretion, cardiac rhythm, and muscle contraction. The human body expresses a multitude of ion channel types, each with distinct roles in cellular communication. The Sack lab investigates these channels' fundamental mechanisms and engineers molecular tools to both visualize and manipulate electrophysiological activity. We leverage these tools to reprogram neuronal electrical signaling relevant to a wide spectrum of clinical disorders—from cardiac arrhythmias to chronic pain. Our work focuses on selectively modulating ion channel activity to restore or enhance physiological functions. By finding modulators that alter the fundamental stimulus-response characteristic of channel function, we can reprogram neuronal electrical signaling for precise therapeutic benefits.

Imaging Ion Channel Activity in Real Time

Because ion channels open and close at speeds of hundreds of times per second, capturing their dynamics requires sophisticated techniques beyond conventional medical imaging. We have introduced novel probes that bind selectively to specific ion channel conformations, enabling us to visualize channel activity in real time without necessitating genetic or chemical modifications to the channels themselves. By conjugating these probes to fluorescent reporters and exploiting cutting-edge fluorescence microscopy, we can directly observe changes in ion channel behavior. This approach offers an unprecedented look at the electrical underpinnings of physiological and pathological states.