Screening anti-inflammatory compounds in injured spinal cord with microarrays: a comparison of bioinformatics analysis approaches

Pan, Jonathan Z.; Jörnsten, Rebecka; Hart, Ronald P.

doi:10.1152/physiolgenomics.00177.2003

Cited by 24 publications

(12 citation statements)

References 74 publications

(100 reference statements)

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“…The pattern of transcript expression was highly orchestrated from 1 to 90 d after injury and consistent in two distinct rat strains. As seen with thoracic contusions (Carmel et al, 2001;Song et al, 2001;Nesic et al, 2002;Tachibana et al, 2002;Di Giovanni et al, 2003;Pan et al, 2004), a profound loss of neural gene expression was observed by 1 d post-SCI. In our longitudinal study, a very modest rebound occurred by 90 d postinjury, reflective of neural tissue loss within the lesion.…”

Section: Discussionmentioning

confidence: 93%

“…Other SCI microarray (Carmel et al, 2001;Song et al, 2001;Tachibana et al, 2002;Pan et al, 2004) and directed studies (Popovich et al, 1996;Huang et al, 1999;Bethea, 2000;Bethea and Dietrich, 2002;Jones et al, 2002;Pan et al, 2002;Schwartz and Hauben, 2002;Hausmann, 2003) have shown that inflammation plays a major role in acute SCI. Our dataset further demonstrates the apparent regulatory roles of major cytokine families, the extensive orchestration of the immune response, its interrelationship with repair gene families, and a previously unreported persistence of this response in the subacute and chronic stages of SCI (Table 1, supplemental material, available at www.jneurosci.org).…”

Section: Discussionmentioning

confidence: 99%

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Patterns of Gene Expression Reveal a Temporally Orchestrated Wound Healing Response in the Injured Spinal Cord

Velardo¹,

Bürger²,

Williams³

et al. 2004

J. Neurosci.

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Spinal cord injury (SCI) induces a progressive pathophysiology affecting cell survival and neurological integrity via complex and evolving molecular cascades whose interrelationships are not fully understood. The present experiments were designed to: (1) determine potential functional interactions within transcriptional expression profiles obtained after a clinically relevant SCI and (2) test the consistency of transcript expression after SCI in two genetically and immunologically diverse rat strains characterized by differences in T cell competence and associated inflammatory responses. By interrogating Affymetrix U34A rat genome GeneChip microarrays, we defined the transcriptional expression patterns in midcervical contusion lesion sites between 1 and 90 d postinjury of athymic nude (AN) and Sprague Dawley (SD) strains. Stringent statistical analyses detected significant changes in 3638 probe sets, with 80 genes differing between the AN and SD groups. Subsequent detailed functional categorization of these transcripts unveiled an overall tissue remodeling response that was common to both strains. The functionally organized gene profiles were temporally distinct and correlated with repair indices observed microscopically and by magnetic resonance microimaging. Our molecular and anatomical observations have identified a novel, longitudinal perspective of the post-SCI response, namely, that of a highly orchestrated tissue repair and remodeling repertoire with a prominent cutaneous wound healing signature that is conserved between two widely differing rat strains. These results have significant bearing on the continuing development of cellular and pharmacological therapeutics directed at tissue rescue and neuronal regeneration in the injured spinal cord.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Patterns of Gene Expression Reveal a Temporally Orchestrated Wound Healing Response in the Injured Spinal Cord

Velardo¹,

Bürger²,

Williams³

et al. 2004

J. Neurosci.

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“…Relative quantitation of spleen mRNA for the T-cell cytokines IFN␥ and IL-2 used a validated quantitative reverse transcription (RT)-PCR method as described previously by others at the Keck Center for Collaborative Neuroscience, Rutgers University (Pan et al, 2004). Wild-type (n ϭ 8) and mutant (n ϭ 8) mice were given injections of saline (n ϭ 4/strain) or 10 g of SEA (n ϭ 4/strain), and the spleens removed 2 h later.…”

Section: Reverse Transcription and Real-time Pcr For Splenic Ifn-␥ Anmentioning

confidence: 99%

Neuronal, Endocrine, and Anorexic Responses to the T-Cell Superantigen Staphylococcal Enterotoxin A: Dependence on Tumor Necrosis Factor-α

Rossi-George

Urbach²,

Colas³

et al. 2005

J. Neurosci.

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Staphylococcal enterotoxin A (SEA) is a microbial superantigen that activates T-lymphocytes and induces production of various cytokines, including tumor necrosis factor-␣ (TNF␣). Previously, it was shown that SEA activates the hypothalamic-pituitary-adrenal axis and augments gustatory neophobic behaviors. In the present study, it was hypothesized that these effects involve neuronal activation in forebrain regions mediating fear and/or anxiety and are dependent on the production of TNF␣. Male C57BL/6J mice were given intraperitoneal injections of 10 g of SEA and 5 g of lipopolysaccharide (LPS) or saline and perfused 2 h later for histochemical determination of brain c-Fos immunoreactivity (IR). The results showed increased c-Fos IR in the paraventricular nucleus, arcuate nucleus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and lateral septum. Challenge of TNF Ϫ/Ϫ mice with SEA did not produce a significant increase in brain c-Fos IR, although c-Fos was increased after exposure to a psychogenic stressor (i.e., open field). In additional experiments, the elevated corticosterone response to SEA was abrogated in TNF Ϫ/Ϫ mice and was shown to be corticotropin-releasing hormone dependent. Finally, the augmented reduction in novel food intake after SEA challenge was attenuated in TNF Ϫ/Ϫ mice as well as in wild-type mice administered antibody to TNF␣. In conclusion, challenge with SEA recruits brain regions mediating stress and anxiety responses, an effect that requires endogenous TNF␣. Whether this is indicative of all T-cell superantigens remains to be determined, although it stands in contrast to other models of neuroimmunomodulation (e.g., LPS) that involve multiple cytokine influences.

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“…A previous study used microarray approach to assess the genes involved in anti-inflammatory responses in a spinal cord injury model [28]. The anti-inflammatory response is an important component of secondary tissue damage following spinal cord injury.…”

Section: Discussionmentioning

confidence: 99%

“…To circumvent this limitation, we have recently sequenced more than 10, 000 ESTs (expression sequence tags) from the CNS transcriptome of L. stagnalis [20] and established the largest neuronal EST database in Lymnaea (http://www.lymnaea.org). In combination with the availability of the microarray technology [28,29], these gene sequences provide us with the opportunity to perform a high-throughput screening for altered gene expression levels following nerve injury in L. stagnalis . In this study, we have designed the first microarray chip covering 10, 333 known L. stagnalis genes to profile the gene expression patterns following CNS injury.…”

Section: Introductionmentioning

confidence: 99%

Identification of the role of C/EBP in neurite regeneration following microarray analysis of a L. stagnalisCNS injury model

Aleksic

Feng

2012

BMC Neurosci

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BackgroundNeuronal regeneration in the adult mammalian central nervous system (CNS) is severely compromised due to the presence of extrinsic inhibitory signals and a reduced intrinsic regenerative capacity. In contrast, the CNS of adult Lymnaea stagnalis (L. stagnalis), a freshwater pond snail, is capable of spontaneous regeneration following neuronal injury. Thus, L. stagnalis has served as an animal model to study the cellular mechanisms underlying neuronal regeneration. However, the usage of this model has been limited due to insufficient molecular tools. We have recently conducted a partial neuronal transcriptome sequencing project and reported over 10,000 EST sequences which allowed us to develop and perform a large-scale high throughput microarray analysis.ResultsTo identify genes that are involved in the robust regenerative capacity observed in L. stagnalis, we designed the first gene chip covering ~15, 000 L. stagnalis CNS EST sequences. We conducted microarray analysis to compare the gene expression profiles of sham-operated (control) and crush-operated (regenerative model) central ganglia of adult L. stagnalis. The expression levels of 348 genes were found to be significantly altered (p < 0.05) following nerve injury. From this pool, 67 sequences showed a greater than 2-fold change: 42 of which were up-regulated and 25 down-regulated. Our qPCR analysis confirmed that CCAAT enhancer binding protein (C/EBP) was up-regulated following nerve injury in a time-dependent manner. In order to test the role of C/EBP in regeneration, C/EBP siRNA was applied following axotomy of cultured Lymnaea PeA neurons. Knockdown of C/EBP following axotomy prevented extension of the distal, proximal and intact neurites. In vivo knockdown of C/EBP postponed recovery of locomotory activity following nerve crush. Taken together, our data suggest both somatic and local effects of C/EBP are involved in neuronal regeneration.ConclusionsThis is the first high-throughput microarray study in L. stagnalis, a model of axonal regeneration following CNS injury. We reported that 348 genes were regulated following central nerve injury in adult L. stagnalis and provided the first evidence for the involvement of local C/EBP in neuronal regeneration. Our study demonstrates the usefulness of the large-scale gene profiling approach in this invertebrate model to study the molecular mechanisms underlying the intrinsic regenerative capacity of adult CNS neurons.

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Screening anti-inflammatory compounds in injured spinal cord with microarrays: a comparison of bioinformatics analysis approaches

Cited by 24 publications

References 74 publications

Patterns of Gene Expression Reveal a Temporally Orchestrated Wound Healing Response in the Injured Spinal Cord

Patterns of Gene Expression Reveal a Temporally Orchestrated Wound Healing Response in the Injured Spinal Cord

Neuronal, Endocrine, and Anorexic Responses to the T-Cell Superantigen Staphylococcal Enterotoxin A: Dependence on Tumor Necrosis Factor-α

Identification of the role of C/EBP in neurite regeneration following microarray analysis of a L. stagnalisCNS injury model

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