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Molecular mechanisms of growth cone invasion

生长锥侵袭的分子机制

基本信息

批准号：
9768584
负责人：
Timothy M Gomez
金额：
$ 34.03万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768584
关键词：
3-Dimensional Actins Affect Afferent Neurons Axon Brain Cell Adhesion Molecules Cells Chimeric Proteins Cleaved cell Cognitive deficits Collagen Cues Data Dendrites Destinations Detection Development Dimensions Disintegrins Dorsal Dyslexia EMS1 gene Electron Microscopy Embryo Embryonic Development Environment Extracellular Matrix Degradation F-Actin Filopodia Fluorescence Fluorogenic Substrate Gel Genes Growth Cones Growth Factor Human Image Imaging Techniques In Vitro Individual Interneurons Ligands Location MMP2 gene MMP9 gene Mediating Mental disorders Metalloproteases Microscopy Molecular Morphogenesis Morphology Motor Neurons Mutation Nerve Nervous system structure Neural Crest Cell Neurites Neurodevelopmental Disorder Neuroglia Neurons Peptide Hydrolases Process Protein Tyrosine Kinase Proteins Publishing Regulation Research Resolution Role SH3 Domains Sensory Series Signal Transduction Source Spinal Cord Structure Surface Synapses Testing Time Tissues Western Blotting Work Xenopus Zebrafish autism spectrum disorder axon guidance axonal guidance base cell motility cellular imaging confocal imaging fluorescence imaging gain of function genetic regulatory protein in vivo in vivo evaluation live cell imaging loss of function migration nervous system development neural network neurodevelopment neuronal circuitry polymerization receptor three dimensional cell culture two-dimensional

项目摘要

Project Summary The development of the nervous system requires the proper differentiation, migration, morphogenesis and maturation of neurons. The morphological differentiation of individual neurons and assembly of the trillions of neuronal connections that compose the human nervous system occurs through guided extension of axons and dendrites. The long-term objective of our research is to better understand the intracellular signaling cascades and effector mechanisms that are responsible for axon outgrowth and guidance in the developing brain. For this we must understand how nerve growth cones detect, integrate and respond to soluble, as well as cell- and substratum-associated guidance molecules in their environment. Mutations in genes involved in the detection and transduction of axon guidance information into directed neurite outgrowth are responsible for many neuro- developmental disorders, including autisms, dyslexias, psychological disorders and cognitive deficits. Therefore, our work aimed at better understanding the molecular basis of normal neural development, may help inform treatments for conditions leading to abnormal neural network assembly. While extensive studies have investigated the molecular mechanisms that regulate axon guidance over two- dimensional substrata in vitro or along axonal tracks in vivo, little is known about the signals that control axon guidance across three-dimensional tissues. Our preliminary and recently published data suggest that along with planar filopodia and lamellipodia, growth cones generate orthogonal protrusions in vitro and in vivo that resemble podosomes or invadopodia. Podosomes and invadopodia, collectively referred to as invadosomes, are actin-based cellular protrusions associated with extracellular matrix (ECM) degradation and tissue invasion. We hypothesize that growth cone invadosomes function to actively detect ligands through receptor interactions that regulate actin polymerization and participate in ligand and receptor degradation to modulate ligand-mediated guidance. The three aims of this proposal will use a series of molecular gain of function and loss of function manipulations, together with super resolution three-dimensional fluorescence imaging, to assess the signals that control invadosome formation and their roles in controlling neural network formation.

项目总结