Regulation of Olfactory Signal Transduction

嗅觉信号转导的调节

• 批准号: 8439384
• 负责人: HAIQING ZHAO
• 金额: $ 43.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-27 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439384
• 关键词: Afferent Neurons; Attenuated; Binding Sites; Calcium; Calmodulin; Cells; Cilia; Coupled; Cyclic AMP; Defect; Exhibits; Feedback; Food; Functional disorder; GTP-Binding Proteins; Genetic; Goals; Grant; Individual; Investigation; Kinetics; Knock-out; Knowledge; Lead; Mediating; Mediator of activation protein; Membrane Potentials; Minor; Molecular; Molecular Genetics; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Neurons; Odors; Olfaction Disorders; Olfactory Epithelium; Partner in relationship; Pathway interactions; Phenotype; Phosphorylation; Phosphorylation Site; Physiological; Physiology; Process; Quality of life; Recovery; Regulation; Research; Rest; Role; Sensory; Signal Transduction; Smell Perception; Speed; System; Testing; adenylyl cyclase III; base; cyclic-nucleotide gated ion channels; desensitization; insight; mouse model; mutant; novel; phosphoric diester hydrolase; public health relevance; research study; response

DESCRIPTION (provided by applicant): Olfactory transduction is the process by which olfactory sensory neurons (OSNs) transform odor information into neuronal electrical signals. Over the past two and a half decades, extensive investigations have led to the elucidation of a core transduction pathway in vertebrate OSNs. However, the processes that regulate transduction to allow for proper sensitivity and response kinetics are not well understood. Calcium is a key olfactory transduction regulator. Calcium enters the sensory cilium through the olfactory cyclic nucleotide-gated (CNG) channel during the odor response, amplifies OSN depolarization, and also negatively regulating several olfactory transduction components. This negative regulation governs OSN adaptation--a phenomenon manifested as reduced sensitivity upon sustained or repeated stimulation. In this proposal, we propose to take advantage of multiple genetically modified mouse strains that we generated to: 1) investigate the integration of multiple Ca2+-dependent feedback mechanisms in OSN adaptation (Aim 1); and 2) investigate the role of negative regulatory mechanisms, which function in termination and adaptation, in setting OSN sensitivity at rest (Aim 2). Electrophysiological analysis, at the level of intact olfactory epithelium and the isolated single cell level, will be conducted on mice carrying double or triple mutations for calcium-dependent feedback mechanisms (Aim 1) as well as on mice that lack a calcium-dependent feedback mechanism and also lack efficient calcium extrusion (Aim 2). The long-term goal of this proposal is to elucidate the molecular mechanisms underlying olfaction. The proposed investigation will lead to a better understanding of how OSNs encode the intensity and temporal features of odor stimulations by regulating sensitivity and response kinetics. The knowledge gained from the proposed research will enhance our understanding of normal olfactory function and olfactory dysfunctions.

描述（由申请人提供）：嗅觉转导是嗅觉感觉神经元（OSN）将气味信息转化为神经元电信号的过程。在过去的两十年中，广泛的研究导致脊椎动物OSN中的核心转导途径阐明了。但是，调节转导以允许适当敏感性和反应动力学的过程尚不清楚。钙是关键的嗅觉转导调节剂。钙通过嗅觉循环核苷酸门控（CNG）通道进入气味响应期间的感觉纤毛，放大OSN去极化，并负调节几个嗅觉转导组件。这种负调节控制了OSN适应 - 这种现象表现为持续或反复刺激时的灵敏度降低。在此提案中，我们建议利用多种遗传修饰的小鼠菌株，我们生成：1）研究OSN适应中多个CA2+依赖性反馈机制的整合（AIM 1）； 2）研究负调控机制在终止和适应中起作用，在设定OSN静止敏感性中的作用（AIM 2）。电生理分析，在该水平上 完整的嗅觉上皮和孤立的单细胞水平将在携带双重或三重突变的小鼠上进行，以用于钙依赖的反馈机制（AIM 1），以及缺乏钙依赖性反馈机制且缺乏有效钙挤出的小鼠（AIM 2）。该提案的长期目标是阐明嗅觉的基础机制。提出的研究将通过调节灵敏度和响应动力学来更好地理解OSN如何编码气味刺激的强度和时间特征。从拟议的研究中获得的知识将增强我们对正常嗅觉功能和嗅觉功能障碍的理解。