Modulation of Olfactory Bulb Neuron Current Properties

嗅球神经元电流特性的调节

基本信息

批准号：
8272613
负责人：
DEBRA Ann FADOOL
金额：
$ 26.47万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-01-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8272613
关键词：
Action Potentials Adaptor Signaling Protein Affect Alzheimer&apos s Disease American Axon Behavior Behavioral Biochemical Body Weight Caloric Restriction Cells Chemistry Code Complex Diabetes Mellitus Diet Discrimination Down-Regulation Drug Delivery Systems Electrophysiology (science)Energy Metabolism Fatty acid glycerol esters Frequencies Gated Ion Channel Gene Targeting Genetic Models Glucose Health Homeostasis Hormones Insulin Insulin Receptor Insulin Resistance Investigation Ion Channel Knockout Mice Ligands Link Mediating Melanocortin 4 Receptor Membrane Potentials Metabolic Diseases Molecular Mus Mutant Strains Mice Neurodegenerative Disorders Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Odorant Receptors Odors Overweight Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Physiological Physiology Plastics Potassium Potassium Channel Process Property Protein Biochemistry Proteins Receptor Protein-Tyrosine Kinases Regulation Research Resistance Role Scorpions Sensory Serum Shapes Signal Transduction Signaling Protein Smell Perception Stream Surveys Synapses System Toxin Transgenic Mice Weight Weight Gain Work Workload base design feeding genetic regulatory protein glucose transport heart circulation interdisciplinary approach mouse model neuron development neuroregulation novel olfactory bulb olfactory threshold protein protein interaction receptor scaffold ubiquitin ligase voltage

项目摘要

Description (provided by applicant): Ion channels are a component of multiprotein scaffolds regulated by molecular protein-protein interactions to control electrical excitability of neurons and provide proper subcellular adjacencies to downstream cell signaling machinery. The work in this proposal will focus upon non-traditional roles of a voltage-gated ion channel (Kv1.3) predominantly expressed in mitral cell neurons of the olfactory bulb to understand the contribution of voltage-gated activity to olfactory coding. The recently uncovered, multifarious role for K channels - including energy homeostasis, axon targeting, and development of neuronal cytoarchitecture - is poorly understood. A multidisciplinary approach using transgenic mouse models (odorant receptor-tagged mice, Kv1.3-null mice, YFP mitral cell mice, and MC4R-null mice) to study Kv1.3 activity is proposed incorporating the METHODS of olfactory bulb electrophysiology, protein biochemistry, intranasal hormone/drug delivery, olfactory discrimination (behavior), systems physiology, and anatomical analysis of olfactory circuitry as a means for determining the mechanistic details and global physiological effects of neuromodulation of voltage-gated activity in the olfactory bulb. The SPECIFIC AIMS of this proposal are based on three HYPOTHESES: 1. Interactions with signaling proteins in the insulin receptor kinase/phosphatase cascade regulate Kv1.3 ion channel activity. 2. Voltage-gated activity from Kv1.3 ion channels modulates olfactory bulb mitral cell activity and olfactory acuity. 3. Gene-targeted deletions of Kv1.3 channel protein and the melanocortin 4 receptor will provide mechanistic details of how this potassium channel regulates energy homeostasis that modulates olfactory sensory ability via glucose utilization. The broad, long-term OBJECTIVE of this research is to elucidate how neuromodulation of voltage-gated ion channel activity can give rise to diverse functions in the olfactory system such as long-term plastic changes in synaptic efficacy, links to energy metabolism, or to fine tune the expression of odorant receptors and their central targets. Understanding the general principles of how ion channels are regulated by well defined molecules enriched in the olfactory system and involved in metabolic disorders (diabetes) and neurodegenerative diseases (Alzheimer's) and why gene-targeted deletion of Kv1.3 increases olfactory ability and induces resistance to weight gain, holds great translational promise as a target for increasing odor discrimination or lessening imbalance in energy homeostasis (obesity). PUBLIC HEALTH RELEVANCE: 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 olfactory ability and obesity?

描述（由申请人提供）：离子通道是多蛋白支架的组成部分，受分子蛋白-蛋白相互作用的调节，以控制神经元的电兴奋性，并为下游细胞信号传导机制提供适当的亚细胞邻接。该提案中的工作将重点关注主要在嗅球二尖瓣细胞神经元中表达的电压门控离子通道（Kv1.3）的非传统作用，以了解电压门控活动对嗅觉编码的贡献。最近发现的 K 通道的多种作用——包括能量稳态、轴突靶向和神经元细胞结构的发育——人们知之甚少。提出使用转基因小鼠模型（气味受体标记小鼠、Kv1.3 缺失小鼠、YFP 二尖瓣细胞小鼠和 MC4R 缺失小鼠）结合嗅球电生理学、蛋白质生物化学方法来研究 Kv1.3 活性的多学科方法、鼻内激素/药物输送、嗅觉辨别（行为）、系统生理学和嗅觉回路的解剖分析作为确定嗅球电压门控活动神经调节的机制细节和整体生理效应。该提案的具体目标基于三个假设： 1. 与胰岛素受体激酶/磷酸酶级联中信号蛋白的相互作用调节 Kv1.3 离子通道活性。 2. Kv1.3 离子通道的电压门控活性调节嗅球二尖瓣细胞活性和嗅觉敏锐度。 3. Kv1.3通道蛋白和黑皮质素4受体的基因靶向删除将提供该钾通道如何调节能量稳态的机制细节，从而通过葡萄糖利用来调节嗅觉感觉能力。这项研究的广泛、长期目标是阐明电压门控离子通道活动的神经调节如何在嗅觉系统中产生多种功能，例如突触功效的长期可塑性变化、与能量代谢的联系，或微调气味受体及其中心靶标的表达。了解离子通道如何受到嗅觉系统中丰富的明确分子调节并参与代谢紊乱（糖尿病）和神经退行性疾病（阿尔茨海默病）的一般原理，以及为什么基因靶向删除 Kv1.3 会增加嗅觉能力并诱导对嗅觉的抵抗力体重增加作为增加气味辨别力或减少能量稳态失衡（肥胖）的目标具有巨大的转化前景。公共卫生相关性：65% 的美国人超重；不必要的体重增加会导致心脏和循环系统负荷增加，增加胰岛素抵抗，并引发 II 型糖尿病。该提案旨在阐明嗅球中表达的离子通道如何参与体重和能量代谢的基本细胞机制；嗅觉能力和肥胖之间有联系吗？