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认为是神经元兴奋性的抑制剂，是驱动静息膜电位和spike放电频率的主要蛋白质。已经发现，自然或疾病驱动的嗅球敏感性变化在钾通道水平上受到监测，因此可能有助于身体对传统下丘脑轴以外的大脑区域的脂肪摄入，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今后内分泌学和感觉系统界面的研究方向提供知识基础。最新的统计报告显示，65%的美国人超重，而饮食引起的糖尿病或II型糖尿病正在我们的人群中流行，在美国儿童中比例不成比例地上升。本研究的方法将采用跨学科的方法，通过电生理学、解剖学（基因可识别的）神经元跟踪和系统生理学（代谢、摄取行为）来研究嗅球是如何被设计成体重和能量稳态的代谢传感器的。该研究的创新之处在于，稳定的离子通道肽将通过鼻内和手术植入渗透微型泵输送，以通过阻断嗅球中的钾通道传导来评估代谢的增加。该研究的具体目的基于三个假设：1)通道的管腔阻塞对基础代谢和活动依赖性代谢的影响不同；2)能量可用性影响嗅觉感觉图谱的发育和表达突触后目标的通道的功能；3)嗅球中动作电位产生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，从而为肥胖和相关代谢紊乱提供翻译治疗，同时影响化学感受器的感觉生理。

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.