Obesity has become an epidemic throughout the world and therapeutics to mitigate this have yet to be successfully developed. In recent years, the relationship between olfaction and metabolic function has become apparent. A variety of metabolic cues alter olfactory behavior by modulating signaling within the olfactory bulb (OB). Likewise, gene-target deletion in mice of the voltage-gated ion channel Kv1.3 yields increased excitability of the primary projection neurons in the OB and a concomitant OB dependent increase in metabolism. The PRIMARY GOAL of this proposal is to determine if targeted disruption of Kv1.3 in the OB can alter metabolism, in turn proving to be a potential therapeutic target for obesity and other metabolic disorders. The METHODS of this proposal are highly interdisciplinary, applying electrophysiology (heterologous expression and traditional slice), pharmacology, nanoparticle technology, drug delivery (surgical implantation of osmotic mini-pumps and intranasal delivery), drug tracking (magnetic resonance imaging), and metabolic assessment.
The SPECIFIC AIMS of this proposal are based upon two HYPOTHESES: 1) Addition of an magnetic nanoparticle to a Kv1.3 inhibitor will lead to increased concentrations retained within the olfactory bulb during application of magnetic field and will allow for trackingof the drug vector's distribution throughout the brain with magnetic resonance imaging, and 2) A targeted reduction of Kv1.3 conductance will alter electrical activity in the olfactory bulb, in tun increasing metabolism and reducing body weight. The work in this proposal will develop a nanoparticle drug vector and its pharmacological properties will be determined using patch-clamp electrophysiology. Following delivery of the drug vector to mice, in-vivo magnetic resonance imaging will be performed such that targeted delivery towards the OB can be confirmed and optimized. To determine the drug vector's effect on metabolic function, animals will be housed in custom engineered metabolic chambers while drug delivery is being performed. This work aims to both determine if targeted disruption of Kv1.3 can alter metabolism as well as develop a means of targeted drug delivery towards the OB.
Obesity has become a major problem worldwide. Feeding behavior is largely regulated by olfaction and more recently olfaction's relationship to metabolic function is becoming apparent. This proposal is designed to determine if altering olfactory activity can influence metabolism and to simultaneously develop a means of targeted drug delivery towards the olfactory bulb.
| Schwartz, Austin B; Kapur, Anshika; Wang, Wentao et al. (2017) Margatoxin-bound quantum dots as a novel inhibitor of the voltage-gated ion channel Kv1.3. J Neurochem 140:404-420 |
