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: 8011304
• 负责人: RANDALL R REED
• 金额: $ 40.04万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011304
• 关键词: Afferent Neurons; Axon; Bardet-Biedl Syndrome; Biogenesis; Brain; Carrier Proteins; Cell Death; Cell physiology; Cell surface; Cells; Cellular Structures; Chemicals; Cilia; Complement; Complex; Detection; Development; Disease model; Dissection; Evolution; Failure; Family; Foundations; G Protein-Coupled Receptor Genes; Gene Mutation; Genetic; Hereditary Disease; Human; Human Genetics; In Vitro; Individual; Integral Membrane Protein; Life; 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; novel; olfactory receptor; programs; 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显著敏感性和特异性由此而来