Grant: Foundation Grant

<html> <body>Chronic pain is a debilitating condition that reflects a long term sensitization of signal transduction in the afferent pain pathway. We now know that this process involves the dysregulation of voltage-gated calcium channels &ndash; key players that control the neuronal activity along the pain transduction pathway. Calcium channels can influence the excitability of afferent pain fibers, the transmission of pain signals up the spinal cord, as well as the perception of pain in the prefrontal cortex. Based on this concept, our <strong>overarching hypothesis</strong> posits that calcium channels and their regulatory elements can be exploited to identify new pain therapeutics. <strong>Our research</strong> <strong>vision</strong> will encompass three interrelated research aims focused on understanding the function, regulation and dysregulation of calcium channels in pain signaling. These aims will build upon our exciting new findings and unparalleled opportunity to <strong>advance knowledge</strong> and develop more effective pain therapeutics. <br> <br> <strong>Aim#1</strong> focuses on the roles of T-type calcium channels in regulating the electrical excitability of primary afferent pain fibers and their contribution to neurotransmission at synapses in the spinal cord dorsal horn. T-type channels are markedly upregulated in response to nerve injury or peripheral inflammation, resulting in pain hypersensitivity. Our discovery that upregulation is critically dependent on ubiquitination of the channels sets the stage to dissect the molecular regulation of pain hypersensitivity to develop mitigating therapeutic strategies.<br> <br> <strong>Aim#2</strong> focuses on the role of N-type calcium channels in controlling synaptic transmission at dorsal horn synapses. Our work established that the function and trafficking of N-type channels is potently regulated by opioid and opioid-like receptors, contributing to the development of opioid tolerance. Here we will identify how interactions between opioid-like receptors and N-type channels upregulate channel density at synaptic terminals and thus synaptic function. We will then apply this information to develop improved treatment strategies for pain.<br> <br> <strong>Aim #3</strong> focuses on investigating how calcium channels in GABAergic neurons influence pain perception in prefrontal cortex. This aim is based on our preliminary data suggesting that prefrontal GABAergic neurons can contribute to the development of chronic pain. This unexpected finding points us to a novel research direction to better understand the role of calcium channels in higher order pain processing, and to develop more effective treatments to mitigate refractive chronic pain conditions. <br> <br> The <strong>core expertise</strong> will include molecular biology, biochemistry, electrophysiology, image analysis, <em>in vitro</em> recordings in brain slice and expression systems, optogenetics and <em>in vivo</em> pain measurements, all of which are well established in my lab. At the heart of the research program also lies a team of experts comprised of graduate and postgraduate trainees, research associates, and external collaborators in Calgary and at other international centers. Building on my extensive track record of <strong>training and mentoring</strong> graduate students and postdoctoral fellows, our proposed program will facilitate their development into independent basic and translational scientists. Training activities will be augmented by a superb professional development platform within the Hotchkiss Brain Institute (HBI), and an exceptionally strong Neuroscience graduate program.</body> </html>