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）：纤毛是无处不在的细胞细胞器，对于包括嗅觉在内的许多发育和生理过程至关重要。纤毛生长可能处​​于严格的生物控制之下，因为不同的细胞类型具有不同的数量和长度的纤毛。但是，对于哪些因素调节纤毛形态以及形态如何影响功能，知之甚少。该提案旨在以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。当气味剂与鼻子嗅觉感觉神经元（OSN）纤毛上的气味受体（ORS）结合时，气味检测就开始了。小鼠主嗅觉上皮包含数百万个OSN，每种OSN都以〜1200的曲目表示一种或类型。因此，几千个OSN具有相同或同一性。拟议的研究基于以下有趣的发现，即OSN表达相同或显示纤毛长度的位置依赖性差异。当OSN的子集在整个嗅觉上皮中标记为特定标记时，发现纤毛长度为 平均在鼻腔隔膜前后的〜2？m增加到〜14？m。值得注意的是，纤毛长度模式与鼻腔中的气味吸收正相关，而纤毛较长的OSN对气味刺激更敏感。建立和维持纤毛模式并不需要感官体验和神经元活动，但是ACIII是原发性纤毛的关键嗅觉信号分子和通用标记，在 这个过程。该提案的目的是研究哪些因素可以塑造嗅觉纤毛，以及细胞位置和纤毛长度如何使用免疫组织化学，遗传和电生理工具影响OSN的功能。在此提案中，我将检验两个假设。首先，嗅觉信号传导成分在塑造纤毛长度方面起着新颖和关键作用，与气味诱导的活性无关（AIM 1）。其次，纤毛长和短的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（AIM 2）。结果将为感觉纤毛和编码的结构和功能提供新的见解 气味信息的处理。