Sack_and_Yarov-Yarovoy_Labs

 

Welcome to Vladimir Yarov-Yarovoy and Jon Sack's laboratories. We study new means to observe and control electrophysiological signaling.


VSD gating 2011

 

  • The Yarov-Yarovoy lab focuses on sodium channels.
  • The Sack lab focuses on potassium channels.

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.



Developing new means of imaging and controlling ion channel signaling.

Ion channel proteins in our cell membranes create electrical signals. Ion channels control many physiological processes including hormone secretion, heartbeat, muscle contraction, and neurotransmission. In the Sack lab we study ion channels themselves, as this fundamental physiology research has implications for every electrically excitable cell in our body. Our focus is on creating molecular tools to image and control the physiological activity of specific voltage gated ion channels. These research tools have potential uses for study or treatment of many disease states such as cardiac arrhythmia or neuropathic pain that involve electrical signaling dysfunction.

Seeing ion channel activity

Our ion channels can open and close hundreds of times per second, but this activity has been invisible to medical imaging technologies. We have recently developed methods that, for the first time, enable imaging of ion channel activity without genetic or chemical modification of the channel's structure, and thus have potential as medical diagnostic imaging agents. Our imaging methods involve molecules that bind to ion channels only when they adopt specific conformations. When ion channels change their activity, the probes bind to or dissociate from the channels. We have labeled these probes with fluorescent reporters, so ion channel activity can be imaged by today's radically advancing fluorescence microscope technologies. Ion channel activity probes are a first step towards new medical imaging technology that could diagnose the functioning of specific ion channels in health and disease.

Controlling ion channel activity

The human body expresses hundreds of different types of ion channel proteins. Each channel type has a distinct, unique physiological function. Many physiologic events such as insulin secretion, or pain signaling are driven by a unique complement of ion channels. These processes can be up- or down-regulated by modulating their ion channels. We are developing serial strategies to selectively modulate ion channel types that control specific physiological functions. Our goal is to develop selective ion channel therapies without reduced side-effects that control electrical dysfunctions, such as neuropathic pain.