Potassium ion channels are traditionally viewed as the dampeners of neuronal excitability and are the predominant proteins that drive the resting membrane potential and spike firing frequency. It has been discovered that natural or disease driven changes in the sensitivity of the olfactory bulb are monitored at the level of a potassium channel and thus may contribute to the body's metabolic response to fat intake, hyperglycemia, or energy balance, in a brain region outside the traditional hypothalamic axis. The PRIMARY GOAL of this project is to discover molecules that can block the conduction of the potassium channel in the olfactory bulb leading to changes in metabolism. The influence of metabolic state on olfactory structure/function and energy expenditure at the level of the action potential will provide a knowledge base to extend to future directions of research at the interface between endocrinology and sensory systems. The latest statistics report that 65% of Americans are overweight while diet-induced or type II diabetes is becoming epidemic in our population, rising disproportionately in American children. The METHOD of this study will tackle an interdisciplinary approach whereby electrophysiology, anatomical (genetically identifiable) neuronal tracking, and systems physiology (metabolism, ingestive behaviors) will be applied to investigate how the olfactory bulb is designed as a metabolic sensor of body weight and energy homeostasis. The INNOVATION of the study will be that stable ion channel peptides will be delivered intranasally and via surgically implanted osmotic mini-pumps to assess increases in metabolism by blocking potassium channel conduction in the olfactory bulb.
The SPECIFIC AIMS of the study are based upon three hypotheses: 1) blocking the lumen of the channel can differentially affect basal vs. activity-dependent metabolism, 2) energy availability affects the development of the olfactory sensory map and the function of the channel expressing post-synaptic targets, and 3) energy usage for action potential generation in the olfactory bulb is influenced by the metabolic state of the animal. This study will seek to elucidate the extent to which this particular potassium channel governs energy homeostasis to provide translational therapeutics for obesity and associated metabolic disorders while impacting the sensory physiology of chemoreceptors.
Sixty-five percent of Americans are overweight;unwanted weight gain induces an increased workload on the heart and circulation, increases insulin resistance, and precipitates type II Diabetes. This proposal is designed to elucidate the basic cellular mechanisms of how ion channels expressed in the olfactory bulb are involved in body weight and energy metabolism;is there a link between the function of the olfactory system and obesity?
|McCarthy, Deirdre M; Bell, Genevieve A; Cannon, Elisa N et al. (2016) Reversal Learning Deficits Associated with Increased Frontal Cortical Brain-Derived Neurotrophic Factor Tyrosine Kinase B Signaling in a Prenatal Cocaine Exposure Mouse Model. Dev Neurosci :|
|VÃ©lez, Patricio; Schwartz, Austin B; Iyer, Subashini R et al. (2016) Ubiquitin ligase Nedd4-2 modulates Kv1.3 current amplitude and ion channel protein targeting. J Neurophysiol 116:671-85|
|Spear, John M; Koborssy, Dolly Al; Schwartz, Austin B et al. (2015) Kv1.3 contains an alternative C-terminal ER exit motif and is recruited into COPII vesicles by Sec24a. BMC Biochem 16:16|
|Thiebaud, Nicolas; Johnson, Melissa C; Butler, Jessica L et al. (2014) Hyperlipidemic diet causes loss of olfactory sensory neurons, reduces olfactory discrimination, and disrupts odor-reversal learning. J Neurosci 34:6970-84|