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The role of CFAP69 in olfaction

CFAP69 在嗅觉中的作用

基本信息

批准号：
9913494
负责人：
HAIQING ZHAO
金额：
$ 33.79万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913494
关键词：
Action Potentials Address Adenovirus Vector Affect Afferent Neurons Amino Acids Animal Behavior Animal Model Animals Attenuated Behavior Behavioral Biochemical Biology Brain Cells Chimeric Proteins Cilia Code Cues Electrophysiology (science)Exhibits Family Dasypodidae Fire - disasters Flagella Food Functional disorder Human Inferior Kinetics Knock-out Knockout Mice Knowledge Mass Spectrum Analysis Mediating Membrane Molecular Mus Mutant Strains Mice Mutation Nature Nose Odors Olfactory Epithelium Organism Output Pathway interactions Pattern Performance Peripheral Pharmacology Phase Phenotype Physiology Play Preparation Process Property Proteins Proteomics Protocols documentation Publications Quality of life Receptor Cell Research Role Sensory Sensory Receptors Signal Transduction Site Smell Perception Stimulus System Time base cohesion conditional knockout experimental study fitness in vivo mouse model mutant novel olfactory sensory neurons olfactory stimulus protein protein interaction response temporal measurement

项目摘要

Necessary steps towards understanding the sense of smell include characterizing the relevant molecular components that regulate olfactory sensory neuron (OSN) responses and analyzing behaviors of animal models that harbor abnormal odor coding. Our initial studies in mice suggest that Cilia- and Flagella-Associated Protein 69 (CFAP69), an evolutionarily conserved and poorly studied protein, plays a critical, yet unconventional, role in regulating olfactory transduction kinetics, odor stimuli coding of OSNs and also olfactory behavior. CFAP69 is enriched in OSN cilia, where olfactory signal transduction occurs. OSNs from CFAP69 conditional knockout mice display faster response kinetics in both on- and off- phases of the response with little change in response size, and can fire action potentials more faithfully to repeated stimuli than the control OSNs. CFAP69 conditional knockout mice, despite having higher temporal resolution in coding odor stimuli at the peripheral sensory neuron level, performed inferiorly in a challenging olfactory task. In this proposal, we will: 1) Determine the role of CFAP69 in regulating OSN sensitivity, adaptation and action potential coding by detailed electrophysiological analysis of odor responses at the levels of intact olfactory epithelium and isolated single cells from OSN-specific conditional knockout mice; 2) Investigate the mechanisms by which CFAP69 exerts its effect by using both a combined pharmacological and electrophysiological approach to determine the site of CFAP69 action in the transduction cascade and a biochemical approach to identify its interaction protein partners; and 3) Investigate how altered OSN response and odor stimuli coding affect olfactory behavior in OSN-specific conditional knockout mice. The proposed research will bring new knowledge and new perspective to the understanding of the olfactory transduction process, olfactory stimuli coding of OSNs and olfactory perception. The research will enhance our understanding of the fundamental biology of olfaction and olfactory dysfunction.

理解嗅觉的必要步骤包括表征相关的分子成分调节嗅觉感觉神经元(OSN)反应并分析存在异常的动物模型的行为气味编码。我们在小鼠身上的初步研究表明，纤毛和鞭毛相关蛋白69(CFAP69)是一种进化上的保守但研究很少的蛋白质，在调节嗅觉传导动力学方面发挥着关键但非常规的作用，嗅觉刺激编码OSN以及嗅觉行为。CFAP69富含OSN纤毛，嗅觉信号转导发生了。CFAP69条件性基因敲除小鼠的OSN在开启和关闭状态下都表现出更快的反应动力学反应的不同阶段，反应大小几乎没有变化，并且可以对重复刺激更忠实地激发动作电位而不是控制OSN。CFAP69条件性基因敲除小鼠，尽管在编码气味方面具有更高的时间分辨率外周感觉神经元水平的刺激，在具有挑战性的嗅觉任务中表现不佳。在这项建议中，我们将： 1)确定CFAP69在调节OSN敏感性、适应性和动作电位编码中的作用大鼠完整嗅上皮和分离的单细胞嗅觉反应的电生理学分析 OSN特异性条件性基因敲除小鼠；2)研究CFAP69通过两者发挥作用的机制用药理学和电生理相结合的方法确定CFAP69在转导中的作用部位 CASCADE和生化方法来确定其相互作用蛋白伙伴；以及3)研究OSN反应是如何改变的气味刺激编码影响OSN特异性条件性基因敲除小鼠的嗅觉行为。拟议的研究将为理解嗅觉传导过程、嗅觉刺激带来新知识和新视角 OSNs的编码和嗅觉。这项研究将加深我们对生物多样性的基础生物学的理解。嗅觉和嗅觉功能障碍。