Regulation of Metabolism and the Impact of Obesity for Olfactory Signaling

代谢调节和肥胖对嗅觉信号的影响

• 批准号: 8694298
• 负责人: DEBRA Ann FADOOL
• 金额: $ 29.37万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694298
• 关键词: Action Potentials; Affect; Afferent Neurons; American; Animals; Basal metabolic rate; Behavioral; Body Weight; Brain region; Caloric Restriction; Cells; Chemoreceptors; Child; Chronic; Country; Dependency; Detection; Development; Diabetes Mellitus; Diet; Discrimination; Disease; Drug Delivery Systems; Electrophysiology (science); Endocrine system; Endocrinology; Energy Metabolism; Epidemic; Fatty acid glycerol esters; Feeding behaviors; Frequencies; Functional disorder; Future; Gated Ion Channel; Gene Targeting; Generations; Genetic; Head; Health; Homeostasis; Hyperglycemia; Hypothalamic structure; Implant; Incidence; Insulin Resistance; Intake; Investigation; Ion Channel; Link; Maintenance; Maps; Membrane Potentials; Metabolic; Metabolic Diseases; Metabolism; Methods; Monitor; Mus; Neuromodulator; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Odorant Receptors; Overweight; Peptides; Performance; Pharmaceutical Preparations; Physiology; Population; Potassium Channel; Proteins; Pump; Regulation; Reporting; Research; Resistance; Rest; Resveratrol; Role; Sensory; Sensory Physiology; Shapes; Signal Pathway; Signal Transduction; Stream; Structure; Synapses; System; Therapeutic; Weight Gain; Work; Workload; base; dendrotoxin; design; energy balance; feeding; heart circulation; interdisciplinary approach; knowledge base; knowledge of results; motivated behavior; mouse model; nanoparticle; neuronal excitability; neuroregulation; olfactory bulb; public health relevance; response; sensor; sensory system; statistics; voltage

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.

描述（由申请人提供）：传统上将钾离子通道视为神经元兴奋性的阻尼器，并且是驱动静息膜电位和尖峰发射频率的主要蛋白质。已经发现，在钾通道的水平上监测了自然或疾病驱动的嗅球灵敏度的变化，因此可能有助于在传统下丘脑轴外以外的大脑区域中人体对脂肪摄入，高血糖或能量平衡的代谢反应。该项目的主要目标是发现可以阻止嗅球中钾通道传导的分子，从而导致代谢变化。代谢状态对动作电位水平上嗅觉结构/功能和能量消耗的影响将提供知识基础，以扩展到内分泌学和感觉系统之间接口的未来研究方向。最新的统计数据报道说，有65％的美国人超重，而饮食引起的或II型糖尿病在我们的人群中流行，美国儿童不成比例地增加。这项研究的方法将解决一种跨学科方法，该方法将使用电生理学，解剖学（遗传性）神经元跟踪以及系统生理学（代谢，发明行为）来研究嗅球如何设计为体重和能量稳态的代谢传感器。这项研究的创新将是，稳定的离子通道肽将在鼻内和手术植入渗透的迷你泵进行输送，以通过阻断嗅球中的钾通道传导来评估代谢的增加。该研究的具体目的是基于三个假设：1）阻断通道的管腔可以差异地影响基础与活性依赖性代谢，2）能量可用性影响嗅觉感觉图的发展以及表达后突触后靶标的通道功能，以及3）能够在动物中影响动物的潜在产生能量的能量，该动作是诸如动物效应的。这项研究将寻求阐明该特定钾通道在肥胖症和相关代谢性疾病提供转化疗法的同时，同时影响化学感受器的感觉生理的程度。