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A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program.

Neuron | 2016

The regenerative capacity of the injured CNS in adult mammals is severely limited, yet axons in the peripheral nervous system (PNS) regrow, albeit to a limited extent, after injury. We reasoned that coordinate regulation of gene expression in injured neurons involving multiple pathways was central to PNS regenerative capacity. To provide a framework for revealing pathways involved in PNS axon regrowth after injury, we applied a comprehensive systems biology approach, starting with gene expression profiling of dorsal root ganglia (DRGs) combined with multi-level bioinformatic analyses and experimental validation of network predictions. We used this rubric to identify a drug that accelerates DRG neurite outgrowth in vitro and optic nerve outgrowth in vivo by inducing elements of the identified network. The work provides a functional genomics foundation for understanding neural repair and proof of the power of such approaches in tackling complex problems in nervous system biology.

Pubmed ID: 26898779 RIS Download

Associated grants

  • Agency: NINDS NIH HHS, United States
    Id: NS074430
  • Agency: NINDS NIH HHS, United States
    Id: P30 NS062691
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS074430
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS038253
  • Agency: NICHD NIH HHS, United States
    Id: U54 HD090255

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This is a list of tools and resources that we have found mentioned in this publication.


GeneCopoeia (tool)

RRID:SCR_003145

Commercial organization which provides reagents and services for molecular biology research. Its services include clone collections, microRNA solutions, genome editing, qPCR products, and fluorescent labeling and detection.

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Anti-Synaptophysin 1 (antibody)

RRID:AB_1210382

This polyclonal targets Synaptophysin 1

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Anti-GFP antibody (antibody)

RRID:AB_300798

This polyclonal targets GFP

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Neuronal Class III beta-Tubulin (TUJ1) Monoclonal Antibody, Purified (antibody)

RRID:AB_2313773

This monoclonal targets Neuronal Class III beta-Tubulin (TUJ1) Purified

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TrakEM2 (data processing software)

RRID:SCR_008954

An ImageJ plugin for morphological data mining, three-dimensional modeling and image stitching, registration, editing and annotation. Two independent modalities exist: either XML-based projects, working directly with the file system, or database-based projects, working on top of a local or remote PostgreSQL database. What can you do with it? * Semantic segmentation editor: order segmentations in tree hierarchies, whose template is exportable for reuse in other, comparable projects. * Model, visualize and export 3D. * Work from your laptop on your huge, remote image storage. * Work with an endless number of images, limited only by the hard drive capacity. Dozens of formats supported thanks to LOCI Bioformats and ImageJ. * Import stacks and even entire grids (montages) of images, automatically stitch them together and homogenize their histograms for best montaging quality. * Add layers conveniently. A layer represents, for example, one 50 nm section (for TEM) or a confocal section. Each layer has its own Z coordinate and thickness, and contains images, labels, areas, nodes of 3d skeletons, profiles... * Insert layer sets into layers: so your electron microscopy serial sections can live inside your optical microscopy sections. * Run any ImageJ plugin on any image. * Measure everything: areas, volumes, pixel intensities, etc. using both built-in data structures and segmentation types, and standard ImageJ ROIs. And with double dissectors! * Visualize RGB color channels changing the opacity of each on the fly, non-destructively. * Annotate images non-destructively with floating text labels, which you can rotate/scale on the fly and display in any color. * Montage/register/stitch/blend images manually with transparencies, semiautomatically, or fully automatically within and across sections, with translation, rigid, similarity and affine models with automatically extracted SIFT features. * Correct the lens distortion present in the images, like those generated in transmission electron microscopy. * Add alpha masks to images using ROIs, for example to split images in two or more parts, or to remove the borders of an image or collection of images. * Model neuronal arbors with 3D skeletons (with areas or radiuses), and synapses with connectors. * Undo all steps. And much more...

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NEURON (software resource)

RRID:SCR_005393

NEURON is a simulation environment for modeling individual neurons and networks of neurons. It provides tools for conveniently building, managing, and using models in a way that is numerically sound and computationally efficient. It is particularly well-suited to problems that are closely linked to experimental data, especially those that involve cells with complex anatomical and biophysical properties. NEURON has benefited from judicious revision and selective enhancement, guided by feedback from the growing number of neuroscientists who have used it to incorporate empirically-based modeling into their research strategies. NEURON's computational engine employs special algorithms that achieve high efficiency by exploiting the structure of the equations that describe neuronal properties. It has functions that are tailored for conveniently controlling simulations, and presenting the results of real neurophysiological problems graphically in ways that are quickly and intuitively grasped. Instead of forcing users to reformulate their conceptual models to fit the requirements of a general purpose simulator, NEURON is designed to let them deal directly with familiar neuroscience concepts. Consequently, users can think in terms of the biophysical properties of membrane and cytoplasm, the branched architecture of neurons, and the effects of synaptic communication between cells. * helps users focus on important biological issues rather than purely computational concerns * has a convenient user interface * has a user-extendable library of biophysical mechanisms * has many enhancements for efficient network modeling * offers customizable initialization and simulation flow control * is widely used in neuroscience research by experimentalists and theoreticians * is well-documented and actively supported * is free, open source, and runs on (almost) everything

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STOCK Tg(Thy1-EGFP)MJrs/J (organism)

RRID:IMSR_JAX:007788

Mus musculus with name STOCK Tg(Thy1-EGFP)MJrs/J from IMSR.

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Pvalbtm1(cre)Arbr/Pvalb+; Mapttm2Arbr/Mapt+ (organism)

RRID:MGI:3716104

Allele Detail: Targeted This is a legacy resource.

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B6.Cg-Tg(Thy1-YFP)HJrs/J (organism)

RRID:IMSR_JAX:003782

Mus musculus with name B6.Cg-Tg(Thy1-YFP)HJrs/J from IMSR.

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Nos1tm1.1(cre/ERT2)Zjh/Nos1+ (organism)

RRID:MGI:4947130

Allele Detail: Targeted This is a legacy resource.

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STOCK Slc32a1tm2(cre)Lowl/J (organism)

RRID:IMSR_JAX:016962

Mus musculus with name STOCK Slc32a1tm2(cre)Lowl/J from IMSR.

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ModelDB (data repository)

RRID:SCR_007271

Curated database of published models so that they can be openly accessed, downloaded, and tested to support computational neuroscience. Provides accessible location for storing and efficiently retrieving computational neuroscience models.Coupled with NeuronDB. Models can be coded in any language for any environment. Model code can be viewed before downloading and browsers can be set to auto-launch the models. The model source code has to be available from publicly accessible online repository or WWW site. Original source code is used to generate simulation results from which authors derived their published insights and conclusions.

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WIS-NeuroMath (data processing software)

RRID:SCR_014481

A software tool for automated analysis and quantification of fluorescent microscopy images of nerve cells in vivo and in vitro. The tool also can be used for analysis of cell morphology, neurite length analysis for sections with no cell body, and ganglion explant analysis.

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STRING (data or information resource)

RRID:SCR_005223

Database of known and predicted protein interactions. The interactions include direct (physical) and indirect (functional) associations and are derived from four sources: Genomic Context, High-throughput experiments, (Conserved) Coexpression, and previous knowledge. STRING quantitatively integrates interaction data from these sources for a large number of organisms, and transfers information between these organisms where applicable. The database currently covers 5''214''234 proteins from 1133 organisms. (2013)

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ENCODE (data analysis service)

RRID:SCR_006793

Encyclopedia of DNA elements consisting of list of functional elements in human genome, including elements that act at protein and RNA levels, and regulatory elements that control cells and circumstances in which gene is active. Enables scientific and medical communities to interpret role of human genome in biology and disease. Provides identification of common cell types to facilitate integrative analysis and new experimental technologies based on high-throughput sequencing. Genome Browser containing ENCODE and Epigenomics Roadmap data. Data are available for entire human genome.

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ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

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Cytoscape (software resource)

RRID:SCR_003032

Software platform for complex network analysis and visualization. Used for visualization of molecular interaction networks and biological pathways and integrating these networks with annotations, gene expression profiles and other state data.

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DAVID (software resource)

RRID:SCR_003033

Bioinformatics resource system including web server and web service for functional annotation and enrichment analyses of gene lists. Consists of comprehensive knowledgebase and set of functional analysis tools. Includes gene centered database integrating heterogeneous gene annotation resources to facilitate high throughput gene functional analysis.

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R Project for Statistical Computing (software resource)

RRID:SCR_001905

Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.

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