Regulation of Olfactory Cilia Structure and Function

嗅觉纤毛结构和功能的调节

• 批准号: 8919696
• 负责人: Rosemary Christine Lewis Challis
• 金额: $ 1.58万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-02-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919696
• 关键词: Ablation; Address; Anosmia; Anterior; Ants; Area; Binding; Biological; Biological Process; Biology; Blindness; Brain; Cells; Cilia; Code; Coupled; Cyclic AMP; Cystic kidney; Data; Defect; Detection; Development; Developmental Process; Disease; Dorsal; Dose; Epithelium; Exhibits; Figs - dietary; Fluorescence Microscopy; GTP-Binding Proteins; Generic Drugs; Genetic; Goals; Growth; Health; Image; Immunohistochemistry; Individual; Kidney Diseases; Knowledge; Label; Lead; Length; Liquid substance; Location; Maintenance; Modeling; Morphology; Mus; Nasal cavity; Nasal septum structure; Nasopharynx; Neurons; Normal Pressure Hydrocephalus; Nose; Obesity; Odorant Receptors; Odors; Olfactory Epithelium; Olfactory Pathways; Organ; Organelles; Pattern; Perception; Physiological; Physiological Processes; Play; Process; Regulation; Research; Role; Sagittaria; Sensory; Sensory Process; Shapes; Signal Transduction; Signaling Molecule; Slice; Smell Perception; Solid; Structure; Structure of respiratory epithelium; Tail; Testing; Work; absorption; adenylyl cyclase III; base; brain malformation; cell type; experience; human disease; insight; mouse model; novel; olfactory bulb; olfactory sensory neurons; response; therapy development; tool; vomeronasal organ; young adult

DESCRIPTION (provided by applicant): Cilia are ubiquitous cellular organelles critical for many developmental and physiological processes, including olfaction. Cilia growth is likely under tight biological control since distinct cell types possess cilia with different numbers and lengths. However, little is known about what factors regulate cilia morphology and how morphology impacts function. This proposal aims to address fundamental questions about cilia structure and function using olfactory cilia as a model. Odor detection begins when odorants bind to odorant receptors (ORs) on the cilia of olfactory sensory neurons (OSNs) in the nose. The mouse main olfactory epithelium contains several million OSNs, each of which expresses one OR type out of a repertoire of ~1200. Therefore, a few thousand OSNs share the same OR identity. The proposed research is based on the intriguing discovery that OSNs expressing the same OR display location-dependent differences in cilia length. When subsets of OSNs are labeled with specific markers in the whole-mount olfactory epithelium, the cilia length is found to increase on average from ~2 ?m in the posterior to up to ~14 ?m in the anterior nasal septum. Remarkably, the cilia length pattern is positively correlated with odorant absorption in the nasal cavity, and OSNs with longer cilia are more sensitive to odorant stimulation. Sensory experience and neuronal activity are not required for the establishment and maintenance of the cilia pattern, but ACIII, a key olfactory signaling molecule and generic marker for primary cilia, is essential in this process. The goal of this proposal is to investigate what factors shape olfactory cilia and how cell location and cilia length impact the function of OSNs using immunohistochemical, genetic, and electrophysiological tools. In this proposal, I will test two hypotheses. First, olfactory signaling components play novel and critical roles in shaping cilia length, independent of odor-induced activity (Aim 1). Second, OSNs with long and short cilia have distinct roles in processing odor information depending on the type of stimulation they encounter (Aim 2). The results will offer new insights into the structure and function of sensory cilia and the coding and processing of odor information.

描述（由申请人提供）：纤毛是普遍存在的细胞器，对于许多发育和生理过程（包括嗅觉）至关重要。纤毛的生长可能受到严格的生物控制，因为不同的细胞类型拥有不同数量和长度的纤毛。然而，人们对哪些因素调节纤毛形态以及形态如何影响功能知之甚少。该提案旨在使用嗅觉纤毛作为模型来解决有关纤毛结构和功能的基本问题。当气味剂与鼻子中嗅觉感觉神经元 (OSN) 纤毛上的气味受体 (OR) 结合时，气味检测就开始了。小鼠主嗅上皮含有数百万个 OSN，每个 OSN 表达大约 1200 个 OR 类型中的一种。因此，数千个 OSN 共享相同的 OR 身份。拟议的研究基于一个有趣的发现，即表达相同 OR 的 OSN 在纤毛长度上表现出位置依赖性差异。当 OSN 子集在整个嗅觉上皮细胞中用特定标记进行标记时，发现纤毛长度 平均从后鼻中隔约 2 微米增加到前鼻中隔约 14 微米。值得注意的是，纤毛长度模式与鼻腔中的气味吸收呈正相关，并且纤毛较长的 OSN 对气味刺激更敏感。感觉经验和神经元活动并不是纤毛模式建立和维持所必需的，但 ACIII（一种关键的嗅觉信号分子和初级纤毛的通用标记）对于纤毛模式的建立和维持至关重要。 这个过程。该提案的目标是利用免疫组织化学、遗传和电生理学工具研究哪些因素塑造嗅觉纤毛以及细胞位置和纤毛长度如何影响 OSN 的功能。在这个提案中，我将测试两个假设。首先，嗅觉信号成分在塑造纤毛长度方面发挥着新颖且关键的作用，与气味诱导的活动无关（目标 1）。其次，具有长纤毛和短纤毛的 OSN 在处理气味信息方面具有不同的作用，具体取决于它们遇到的刺激类型（目标 2）。研究结果将为感觉纤毛的结构和功能以及编码和编码提供新的见解。 气味信息的处理。