The role of CFAP69 in olfaction

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）反应并分析具有异常嗅觉感觉神经元的动物模型的行为。 气味编码我们在小鼠中的初步研究表明，纤毛和鞭毛相关蛋白69（CFAP 69），一种进化上的 保守且研究较少的蛋白质，在调节嗅觉传导动力学中起关键但非常规的作用， 气味刺激编码的OSNs和嗅觉行为。CFAP 69富含OSN纤毛，其中嗅觉信号 发生转导。来自CFAP 69条件性敲除小鼠的OSN在开和关两种情况下均显示更快的反应动力学。 反应大小变化不大的反应阶段，并能更忠实地激发动作电位重复刺激 比对照OSN更好。CFAP 69条件性敲除小鼠，尽管在编码气味方面具有更高的时间分辨率 在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出色。在本提案中，我们将： 1)确定CFAP 69在调节OSN敏感性、适应性和动作电位编码中的作用， 在完整的嗅上皮和分离的单细胞水平上的气味反应的电生理学分析， OSN特异性条件性敲除小鼠; 2）通过使用两种方法研究CFAP 69发挥其作用的机制。 结合药理学和电生理学方法来确定CFAP 69在转导中的作用位点， 级联反应和生物化学方法，以确定其相互作用蛋白伴侣;和3）研究如何改变OSN反应 和气味刺激编码影响OSN特异性条件性基因敲除小鼠的嗅觉行为。拟议的研究将 为嗅觉信号转导过程、嗅觉刺激、嗅觉信号转导机制的研究提供了新的知识和视角。 OSN编码和嗅觉感知。这项研究将增强我们对生物学的基本理解。 嗅觉和嗅觉功能障碍。

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.