Regulation of Metabolism and the Impact of Obesity for Olfactory Signaling

描述（由申请人提供）：钾离子通道传统上被视为神经元兴奋性的抑制剂，并且是驱动静息膜电位和尖峰放电频率的主要蛋白质。已经发现，在钾通道的水平上监测嗅球灵敏度的自然或疾病驱动的变化，因此可能有助于身体对传统下丘脑轴外的脑区域中的脂肪摄入、高血糖或能量平衡的代谢反应。该项目的主要目标是发现能够阻断嗅球中钾通道传导的分子，从而导致新陈代谢的变化。代谢状态对嗅觉结构/功能和动作电位水平能量消耗的影响将为内分泌学和感觉系统之间界面的未来研究方向提供知识基础。最新的统计数据显示，65%的美国人超重，而饮食引起的或II型糖尿病正在成为我们人口中的流行病，在美国儿童中不成比例地上升。本研究的方法将解决一个跨学科的方法，即电生理学，解剖（遗传可识别）神经元跟踪和系统生理学（代谢，摄食行为）将被应用于研究嗅球是如何被设计为体重和能量稳态的代谢传感器。本研究的创新之处在于，将通过鼻内和手术植入的渗透微型泵递送稳定的离子通道肽，以通过阻断嗅球中的钾通道传导来评估代谢的增加。本研究的特定目的基于三个假设：1）阻断通道内腔可以不同地影响基础代谢与活动依赖性代谢，2）能量可用性影响嗅觉感觉图的发展和表达突触后靶点的通道功能，3）嗅球中产生动作电位的能量使用受动物代谢状态的影响。本研究将试图阐明这种特殊的钾通道在多大程度上控制能量稳态，为肥胖和相关代谢紊乱提供转化治疗，同时影响化学感受器的感觉生理学。

DESCRIPTION (provided by applicant): 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.