Education & Training
Fellowship, Pediatric Anesthesiology, Vanderbilt University Medical Center (2012)
Residency, Anesthesiology, Vanderbilt University Medical Center (2011)
Transitional Internship, Mayo Clinic (2008)
MD, Vanderbilt University School of Medicine (2007)
BS, Chemistry/Physics, University of West Florida (2000)
Research Project: Attenuation of Pain Perception Through the Targeted Inhibition of SPAK/OSR1
Chronic pain is highly prevalent in the United States, occurring in an estimated 30% of the adult population. The deleterious effects of chronic pain and the risks associated with long-term opioid use have led to a need to investigate new molecules that target specific pathophysiological pain mechanisms. SPAK (Ste20-related Proline Alanine rich Kinase) and OSR1 (Oxidative Stress Response 1 Kinase) are key regulators of ion transport mechanisms such as the Na-K-2Cl (NKCC) and K-Cl (KCC) cotransporters. Through the regulation of ion transport mechanisms involved in Cl- homeostasis, SPAK is known to modulate GABAergic neurotransmission in the both the central and peripheral nervous systems, thereby impacting pain perception. Due to these properties, SPAK and OSR1 are promising targets for novel analgesic drugs. An important characteristic of SPAK and OSR1 is that they contain a conserved carboxyl-terminal (CCT) domain, which recognizes a unique peptide (Arg-Phe-Xaa-Val) motif present in upstream activating kinases (e.g. with-no-lysine kinase 1 (WNK1) and WNK4) as well as its substrates (NKCC1 and KCC2). The binding of this motif to the CCT domain is essential for SPAK/OSR1 function.
Our rationale is that small molecules which interfere with this CCT binding pocket will be highly specific to SPAK/OSR1 kinases and will attenuate the perception of pain. This proposal investigates testable hypotheses which will focus on the computationally screening of various small molecular libraries for novel compounds that favorably bind to the CCT domain using the Rosetta software suite (Aim 1) and validation of CCT-compound complex formation through the use of small molecule 15N NMR (Aim 2). Based on the work from this proposal, we will unearth unique compounds that will disrupt a key pain perception pathway with hopes of adding a new class of medicines to our limited analgesic armamentarium.