The role of CFAP69 in olfaction

CFAP69 在嗅觉中的作用

• 批准号: 10394211
• 负责人: HAIQING ZHAO
• 金额: $ 33.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394211
• 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; Olfactory dysfunction; 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

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.

了解嗅觉的必要步骤包括表征相关分子成分 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。我们对小鼠的初步研究表明，纤毛和鞭毛相关蛋白 69 (CFAP69) 保守且研究较少的蛋白质，在调节嗅觉转导动力学中发挥着关键但非传统的作用， OSN 的气味刺激编码以及嗅觉行为。 CFAP69 富含 OSN 纤毛，其中嗅觉信号 发生转导。 CFAP69 条件敲除小鼠的 OSN 在开启和关闭状态下均表现出更快的响应动力学 反应的各个阶段反应大小几乎没有变化，并且可以更忠实地激发重复刺激的动作电位 比控制 OSN 。 CFAP69 条件敲除小鼠，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较差。在本提案中，我们将： 1) 通过详细确定CFAP69在调节OSN敏感性、适应和动作电位编码中的作用 对完整嗅上皮和分离的单细胞水平的气味反应进行电生理分析 OSN特异性条件敲除小鼠； 2) 利用两者研究CFAP69发挥作用的机制 结合药理学和电生理学方法来确定 CFAP69 在转导中的作用位点 级联和生化方法来识别其相互作用蛋白伙伴； 3) 研究 OSN 响应如何改变 气味刺激编码影响 OSN 特异性条件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 OSN 和嗅觉的编码。该研究将增强我们对基础生物学的理解 嗅觉和嗅觉功能障碍。

项目成果

Intravenous administration of multipotent stromal cells and bone allograft modification to enhance allograft healing.

• DOI: 10.2217/rme-2018-0063
• 发表时间: 2019-02
• 期刊: Regenerative medicine
• 影响因子: 2.7
• 作者: Sharada Paudel;Wen-han Lee;Moses Lee;T. Zahoor;R. Mitchell;Shang-You Yang;Haiqing Zhao;L. Schon-