Data reporting quality and semantic interoperability increase with community-based data elements (CoDEs). Analysis of the open data commons for spinal cord injury (ODC-SCI).

Data interoperability is crucial for effectively combining data for scientific inquiry. To facilitate interoperability, data standards such as a common definition of variables are often developed. The Open Data Commons for Spinal Cord Injury (odc-sci.

Compounds co-targeting kinases in axon regulatory pathways promote regeneration and behavioral recovery after spinal cord injury in mice.

Recovery from spinal cord injury (SCI) and other central nervous system (CNS) trauma is hampered by limits on axonal regeneration in the CNS. Regeneration is restricted by the lack of neuron-intrinsic regenerative capacity and by the repressive microenvironment confronting damaged axons. To address this challenge, we have developed a therapeutic strategy that co-targets kinases involved in both extrinsic and intrinsic regulatory pathways.

Markerless tracking enables distinction between strategic compensation and functional recovery after spinal cord injury.

Injuries to the cervical spinal cord represent around 60% of all spinal cord injuries (SCIs). A major priority for patients with cervical SCIs is the recovery of any hand or arm function. The similarities between human and rodent "reach-to-eat movements" indicate that analyzing mouse forelimb reaching behavior may be a method of identifying clinically relevant treatments for people with cervical SCIs.

Developing and evaluating a team development intervention to support interdisciplinary teams.

Introduction: Incentivizing the development of interdisciplinary scientific teams to address significant societal challenges usually takes the form of pilot funding. However, while pilot funding is likely necessary, it is not sufficient for successful collaborations. Interdisciplinary collaborations are enhanced when team members acquire competencies that support team success.

Phenotypic Screening Following Transcriptomic Deconvolution to Identify Transcription Factors Mediating Axon Growth Induced by a Kinase Inhibitor.

After injury to the central nervous system (CNS), both neuron-intrinsic limitations on regenerative responses and inhibitory factors in the injured CNS environment restrict regenerative axon growth. Instances of successful axon regrowth offer opportunities to identify features that differentiate these situations from that of the normal adult CNS. One such opportunity is provided by the kinase inhibitor RO48, which dramatically enhances neurite outgrowth of neurons in vitro and substantially increased contralateral sprouting of corticospinal tract neurons when infused intraventricularly following unilateral pyramidotomy.

Enriched conditioning expands the regenerative ability of sensory neurons after spinal cord injury via neuronal intrinsic redox signaling.

Overcoming the restricted axonal regenerative ability that limits functional repair following a central nervous system injury remains a challenge. Here we report a regenerative paradigm that we call enriched conditioning, which combines environmental enrichment (EE) followed by a conditioning sciatic nerve axotomy that precedes a spinal cord injury (SCI). Enriched conditioning significantly increases the regenerative ability of dorsal root ganglia (DRG) sensory neurons compared to EE or a conditioning injury alone, propelling axon growth well beyond the spinal injury site.

Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons.

Axon injury is a hallmark of many neurodegenerative diseases, often resulting in neuronal cell death and functional impairment. Dual leucine zipper kinase (DLK) has emerged as a key mediator of this process. However, while DLK inhibition is robustly protective in a wide range of neurodegenerative disease models, it also inhibits axonal regeneration.

AAV8 transduction capacity is reduced by prior exposure to endosome-like pH conditions.

Adeno-associated virus (AAV) is an essential instrument in the neuroscientist's toolkit, which allows delivery of DNA to provide labeling with fluorescent proteins or genetic instructions to regulate gene expression. In the field of neural regeneration, the transduction of neurons enables the observation and regulation of axon growth and regeneration, and in the future will likely be a mechanism for delivering molecular therapies to promote sprouting and regeneration after central nervous system injury. Traditional formulations of AAV preparations permit efficient viral transduction under physiologic conditions, but an improved understanding of the mechanistic limitations of AAV transduction may facilitate production of more resilient AAV strains for investigative and therapeutic purposes.

Computational Identification of Kinases That Control Axon Growth in Mouse.

The determination of signaling pathways and transcriptional networks that control various biological processes is a major challenge from both basic science and translational medicine perspectives. Because such analysis can point to critical disease driver nodes to target for therapeutic purposes, we combined data from phenotypic screening experiments and gene expression studies of mouse neurons to determine information flow through a molecular interaction network using a network propagation approach. We hypothesized that differences in information flow between control and injured conditions prioritize relevant driver nodes that cause this state change.

FAIR SCI Ahead: The Evolution of the Open Data Commons for Pre-Clinical Spinal Cord Injury Research.

Over the last 5 years, multiple stakeholders in the field of spinal cord injury (SCI) research have initiated efforts to promote publications standards and enable sharing of experimental data. In 2016, the National Institutes of Health/National Institute of Neurological Disorders and Stroke hosted representatives from the SCI community to streamline these efforts and discuss the future of data sharing in the field according to the FAIR (Findable, Accessible, Interoperable and Reusable) data stewardship principles. As a next step, a multi-stakeholder group hosted a 2017 symposium in Washington, DC entitled "FAIR SCI Ahead: the Evolution of the Open Data Commons for Spinal Cord Injury research.

Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons.

Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy.

PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.

The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration-competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regeneration-incompetent central spinal cord injury does not. This dichotomic response offers a unique opportunity to investigate the fundamental biological mechanisms underpinning regenerative ability.

Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models.

After a spinal cord injury, axons fail to regenerate in the adult mammalian central nervous system, leading to permanent deficits in sensory and motor functions. Increasing neuronal activity after an injury using electrical stimulation or rehabilitation can enhance neuronal plasticity and result in some degree of recovery; however, the underlying mechanisms remain poorly understood. We found that placing mice in an enriched environment before an injury enhanced the activity of proprioceptive dorsal root ganglion neurons, leading to a lasting increase in their regenerative potential.

Scaffold Ranking and Positional Scanning Identify Novel Neurite Outgrowth Promoters with Nanomolar Potency.

Central nervous system (CNS) neurons typically fail to regrow their axons after injury. Injuries or neuropathies that damage CNS axons and disrupt neuronal circuitry often result in permanent functional deficits. Axon regeneration is therefore an intensely pursued therapeutic strategy for numerous CNS disorders.

The effect of Jun dimerization on neurite outgrowth and motif binding.

Axon regeneration is a necessary step toward functional recovery after spinal cord injury. The AP-1 transcription factor c-Jun has long been known to play an important role in directing the transcriptional response of Dorsal Root Ganglion (DRG) neurons to peripheral axotomy that results in successful axon regeneration. Here we performed ChIPseq for Jun in mouse DRG neurons after a sciatic nerve crush or sham surgery in order to measure the changes in Jun's DNA binding in response to peripheral axotomy.

Can Chromatin Accessibility be Exploited for Axon Regeneration?

Several studies have demonstrated that the intrinsic ability of neurons to regenerate their axons can be stimulated by maneuvers that favor the open state of chromatin, such as inhibiting histone deacetylase activity or increasing histone acetyltransferase activity. Taken together, these experiments suggest that axon regenerative ability can be increased by promoting chromatin accessibility. In this article, we assess the direct evidence in the literature for this hypothesis and re-examine other axon regeneration-promoting manipulations to see if they provide additional support.

Publisher Correction: Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons.

In the version of this Article originally published, the affiliations for Roland A. Fleck and José Antonio Del Río were incorrect due to a technical error that resulted in affiliations 8 and 9 being switched. The correct affiliations are: Roland A.

Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons.

Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1-dependent recruitment of inflammatory cells.

High Content Screening of Mammalian Primary Cortical Neurons.

High Content Screening (HCS) can be used to analyze the morphology of neuronal primary cultures on a large scale. When used in the field of neuronal regeneration this approach allows the screening of hundreds or thousands of perturbagens, such as miRNAs, cDNAs, or compounds, for their ability to induce neuronal growth. One of the most important steps while designing these kinds of experiments is the choice of the correct neuronal model.

Stress Increases Peripheral Axon Growth and Regeneration through Glucocorticoid Receptor-Dependent Transcriptional Programs.

Stress and glucocorticoid (GC) release are common behavioral and hormonal responses to injury or disease. In the brain, stress/GCs can alter neuron structure and function leading to cognitive impairment. Stress and GCs also exacerbate pain, but whether a corresponding change occurs in structural plasticity of sensory neurons is unknown.

Identification of miRNAs involved in DRG neurite outgrowth and their putative targets.

Peripheral neurons regenerate their axons after injury. Transcriptional regulation by microRNAs (miRNAs) is one possible mechanism controlling regeneration. We profiled miRNA expression in mouse dorsal root ganglion neurons after a sciatic nerve crush, and identified 49 differentially expressed miRNAs.

The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury.

The mammalian target of rapamycin (mTOR) positively regulates axon growth in the mammalian central nervous system (CNS). Although axon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR's positive effect on axon growth.