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Mechanisms that maintain and remodel the sensory cilium

维持和重塑感觉纤毛的机制

基本信息

批准号：
9889126
负责人：
Niels Ringstad
金额：
$ 25.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889126
关键词：
Acute Afferent Neurons Behavior Binding Biochemical Biological Assay Blindness Caenorhabditis elegans Carbon Dioxide Cell physiology Cell surface Cells Cellular Membrane Chronic Cilia Cues Cyclic GMP Dendrites Destinations Development Differentiation and Growth Dioxygenases Disease Dynein ATPase Enzymes Esthesia Fluorescence Microscopy Functional disorder Genes Genetic Genetic Screening Genetic Transcription Golgi Apparatus Guanylate Cyclase Homologous Gene Hypoxia Hypoxia Inducible Factor In Situ Integral Membrane Protein Invertebrates Left Life Light Measurement Measures Mediating Membrane Metabolism Microbe Microtubules Modeling Molecular Motor Mutation Nematoda Neurons Odors Organelles Pathway interactions Photoreceptors Physiological Process Proteins Proteome Reproduction Resolution Retinal Degeneration Retinal Diseases Retinal Dystrophy Rhodopsin Role Second Messenger Systems Sensory Signal Transduction Site Stimulus Stress Structure Surface System Testing Transducers Vertebrate Photoreceptors Vesicle atrial natriuretic factor receptor A base cell type disease-causing mutation experimental study extracellular hypoxia inducible factor 1 in vivo novel particle photoreceptor degeneration programs protein transport receptor recruit response tool trafficking vesicle transport

项目摘要

PROJECT SUMMARY Sensory neurons concentrate and organize molecules used to detect environmental stimuli into cilia, which are specialized microtubule-based structures on the cell surface that function as cellular antennas. The proteins that constitute the machinery of sensory transduction are synthesized elsewhere and must be separated from other cellular proteins and transported to the cilium. The importance of mechanisms that mediate trafficking of proteins to the sensory cilium is illustrated by disease-causing mutations that disrupt this process. Mutations that compromise ciliary trafficking of the photopigment rhodopsin or the enzyme guanylyl cyclase cause retinal dystrophies marked by photoreceptor degeneration and, ultimately, blindness. Despite the importance of protein trafficking to the cilium, its underlying molecular mechanisms remain poorly understood. We propose to use chemosensory BAG neurons of the nematode C. elegans as a model for discovery of mechanisms that select and transport cargo destined for the sensory cilium. Like vertebrate photoreceptor neurons, BAG neurons use cyclic GMP as a second messenger for sensory transduction, and the enzymes and effectors that control cyclic GMP signals and turn them into electrical signals are highly similar to those found in photoreceptor neurons. Trafficking of proteins to BAG cilia can be measured in situ using high-resolution fluorescence microscopy assays, and powerful genetic tools are available to acutely or chronically manipulate specific molecular pathways in BAG neurons and determine their function in trafficking to the cilium. Importantly, C. elegans permits discovery of novel factors that mediate ciliary trafficking through genetic screens and biochemical approaches. We propose to use this powerful experimental system to (1) delineate a molecular pathway that matches cargo destined for the sensory cilium with specific motors that will carry it through the dendrite to its destination, and (2) determine how trafficking mechanisms are regulated by physiological or developmental cues that trigger remodeling of the BAG cilium. These studies will advance understanding of a cellular process that is essential for sensory neuron function and viability and will integrate cellular trafficking mechanisms with physiological and developmental programs that impact sensory cilia in vivo.

项目总结