Molecular Genesis and Organization of Olfactory Transduction Components and Cilia

嗅觉传导成分和纤毛的分子起源和组织

• 批准号: 7339305
• 负责人: RANDALL R REED
• 金额: $ 42.73万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339305
• 关键词: Afferent Neurons; Axon; Bardet-Biedl Syndrome; Biogenesis; Brain; Carrier Proteins; Cell Death; Cell physiology; Cell surface; Cells; Cellular Structures; Chemicals; Cilia; Classification; Complement; Complex; Detection; Development; Disease model; Disruption; Dissection; Evolution; Failure; Family; Foundations; G Protein-Coupled Receptor Genes; Gene Mutation; Genetic; Hereditary Disease; Human; In Vitro; Individual; Integral Membrane Protein; Life; Localized; Location; Mammals; Mediating; Membrane; Molecular; Movement; Mus; Mutant Strains Mice; Mutation; Neurons; Odorant Receptors; Olfactory Receptor Neurons; Organelles; Pathogenesis; Pathway interactions; Pattern; Perception; Phenotype; Physiological; Proteins; Receptor Gene; Reporter; Research Personnel; Sensitivity and Specificity; Sensory; Signal Pathway; Signal Transduction; Site; Sorting - Cell Movement; Stimulus; Structure; System; Tissues; Transport Process; Vision; base; cell type; human disease; in vivo; insight; intracellular protein transport; novel; olfactory receptor; programs; protein localization location; protein transport; receptor; receptor function; research study; sensory system; success; trafficking

The remarkable sensitivity and specificity of odorant detection in the mammalian olfactory system derives from highly specialized cellular and molecular components. GPCRs present in the cilia of the olfactory neurons activate a transduction cascade leading to electrical activity and the propagation of sensory information to the brain. The discovery of a large family of olfactory receptor (OR) genes provided an explanation for the differential sensitivity of individual olfactory neurons. Functional expression of ORs in heterologous systems represent an opportunity to define the molecular basis of odorant recognition and has led to modest progress in directing the efficient trafficking of these proteins. However, we know very little about the mechanisms utilized by native sensory neurons to create the highly specialized sensory cilia and localize critical components, including transduction proteins and odorant receptors to these structures. We recently demonstrated that individuals with genetic defects in components of the intraflagellar transport (IFT) system display profound olfactory deficits that are recapitulated in murine models of this disease. These observations provide a foundation for examining the general process of transport in an in vivo system and understanding how specialized integral membrane proteins are moved to specific locations within the cell. We propose to define the molecular apparatus used in sensory neurons to direct the trafficking of signal transduction components. The evolution and structural conservation of olfactory receptors make them uniquely amenable to a systematic dissection of molecular sorting and subcellular localization. We will utilize molecular and functional approaches to visualize and elucidate the dynamics of cilia formation, OR distribution and transduction protein localization. These experiments will complement those derived from in vitro analysis by providing information on receptor trafficking in a native context. These experiments afford new insights into the development of olfactory sensory neurons, pathways for the translocation of tissue-specific proteins to sensory organelles and the establishment of neuronal connectivity. The trafficking of proteins to specific cellular locations and the development of specialized cilia is critical to many cell types in mammals. Our studies should provide valuable new information regarding the pathogenesis of human diseases of sensory perception and cilia-dependent cellular function.

哺乳动物嗅觉系统中气味检测的卓越灵敏度和特异性源于 来自高度专业化的细胞和分子成分。 GPCR 存在于嗅觉纤毛中 神经元激活转导级联，导致电活动和感觉传播 信息传递给大脑。嗅觉受体（OR）基因大家族的发现提供了 解释个体嗅觉神经元的差异敏感性。 OR 的功能表达 异源系统代表了定义气味识别分子基础的机会，并且具有 在指导这些蛋白质的有效运输方面取得了一定进展。然而我们却知之甚少 关于天然感觉神经元用来创建高度专业化的感觉纤毛的机制以及 将关键成分（包括转导蛋白和气味受体）定位到这些结构中。我们 最近证明，鞭毛内运输（IFT）成分存在遗传缺陷的个体 系统表现出严重的嗅觉缺陷，这在这种疾病的小鼠模型中得到了重现。这些 观察为检查体内系统的一般运输过程提供了基础 了解专门的整合膜蛋白如何移动到细胞内的特定位置。 我们建议定义感觉神经元中使用的分子装置来指导信号的运输 转导元件。嗅觉受体的进化和结构保守使它们 独特地适合分子分选和亚细胞定位的系统解剖。我们将利用 分子和功能方法来可视化和阐明纤毛形成的动态，或 分布和转导蛋白定位。这些实验将补充来自 通过提供天然背景下受体贩运的信息进行体外分析。 这些实验为嗅觉感觉神经元的发育、嗅觉通路提供了新的见解。 组织特异性蛋白质易位至感觉细胞器以及神经元的建立 连接性。将蛋白质运输到特定的细胞位置和专门纤毛的发育 对哺乳动物的许多细胞类型至关重要。我们的研究应该提供有关以下方面的有价值的新信息： 人类疾病的发病机制与感觉知觉和纤毛依赖性细胞功能有关。