权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of protein targeting in axon guidance and neuronal morphogenesis

轴突引导和神经元形态发生中蛋白质靶向的调节

基本信息

批准号：
8960783
负责人：
MARY C HALLORAN
金额：
$ 32.73万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8960783
关键词：
Afferent Neurons Alzheimer&apos s Disease Axon Axonal Transport Behavior Binding Biosensor Carrier Proteins Cell membrane Cells Charcot-Marie-Tooth Disease Complex Cues Data Defect Dendrites Development Disease Dynein ATPase Embryo Endosomes Environment Event Goals Human Image Individual Kinesin Label Learning Life Ligands Link Location Maintenance Mediating Mediator of activation protein Membrane Membrane Protein Traffic Memory Microtubules Modeling Molecular Molecular Target Morphogenesis Morphology Motor Natural regeneration Neurodegenerative Disorders Neurons Neurotrophic Tyrosine Kinase Receptor Type 3 Neurotrophin 3 Niemann-Pick Diseases PHluorin Pain Disorder Peripheral Process Protein Family Proteins Regulation Role Route Semaphorin-3A Semaphorins Sensory Signal Transduction Slide Structure System Testing Time Vesicle Vesicle Transport Pathway Zebrafish axon growth axon guidance axon injury extracellular in vivo in vivo Model mutant neural circuit neuron development neuronal cell body neuronal transport neurotrophic factor novel painful neuropathy polymerization protein function protein transport public health relevance receptor research study response synaptogenesis targeted imaging temporal measurement trafficking

项目摘要

DESCRIPTION (provided by applicant): Proper development of neuronal morphology and neural circuits, as well as neuronal maintenance, requires tightly controlled subcellular localization of proteins such as axon guidance cue receptors. Proteins are targeted to specific cell locations by elaborate membrane trafficking and axonal transport systems. Neurons are particularly dependent on high fidelity protein trafficking because of their highly polarized and complex structure. Defects in trafficking and transport underlie multiple human developmental and neurodegenerative diseases, including Alzheimer's disease, Charcot-Marie-Tooth, and Niemann Pick disease. Despite their importance, the mechanisms regulating trafficking processes in neurons are poorly understood, in part due to a paucity of in vivo models in which the machinery and mechanisms of axon transport can be studied. A major challenge to the field and the long term goal of this project is to understand the mechanisms controlling axonal transport and protein localization as neurons develop in their natural environment, where they must integrate multiple extracellular cues. We established a model in which we can image dynamics of neuronal cargo transport, protein localization, and microtubule behavior in the intact zebrafish embryo. Vertebrate sensory neurons extend distinct central and peripheral axons to form the sensory circuit. We found that these axons show distinct responses to axon guidance cues. Moreover, we discovered roles for endosomal trafficking and the kinesin adaptor Calsyntenin-1 (Clstn-1) in differential guidance of sensory axons. In Aim 1 we propose to determine how calsyntenins regulate endosome transport routes to different axon compartments. In Aim 2 we will investigate mechanisms regulating specific localization of receptors for Neurotrophin-3 and Semaphorin3d. We will test the hypothesis that Calsyntenins and another class of kinesin adaptors, the Collapsin response mediator proteins (CRMPs) function to target receptors to specific axon compartments. In Aim 3 we will determine how Clstn-1 and CRMPs organize microtubule polarity and dynamics, processes essential for accurate trafficking and axon growth. Our unique model allows us to connect the molecular events of axonal transport, guidance receptor localization and microtubule organization to specific axon guidance decisions at the time and place they naturally occur. Elucidation of the molecular signals regulating sensory axon growth, guidance, and protein trafficking is critical for understanding neurodegenerative disorders, neuropathic pain disorders and the conditions under which regeneration after axon injury can occur. Our experiments will uncover such mechanisms and thus may help to identify molecular targets for disease treatment.