Our research program investigates the role of astrocytes and in particular astroglial- NF?B in the pathophysiology of neurodegenerative disorders. The experimental aims proposed in this application will test two objectives and are based upon extensive preliminary data. In support of our first objective we have determined there is a significant reduction in oligodendrocyte death, oxidative injury and NADPH oxidase activity following injury. Furthermore, based upon completed and partially confirmed micro array studies, preliminary flow cytometry and immunostaining we have determined that inhibiting astroglial- NF?B greatly modifies the inflammatory environment in the spinal cord such that potentially toxic immunoregulatory molecules along with infiltrating leukocytes are significantly altered in injured TG mice relative to injured WT mice. With respect to the first objective we hypothesize that astrocyte mediated oligodendrocyte death is dependent upon engineering a robust inflammatory environment as well as complex interactions between oxidative pathways and excitotoxicity. In support of our second objective we have significant preliminary data that are very supportive of enhanced oligogenesis. First, we demonstrate there is significantly more white matter in our TG mice following SCI which could be due to reduced oligodendrocyte death (objective 1) and /or oligogenesis. We have also demonstrated there is enhanced myelin gene/protein expression in TG mice following injury, as well as transcription factors known to be important in oligogenesis. Finally it has been previously demonstrated that CXCL12 (SDF-1) and its receptors (CXCR4 and CXCR7) support oligogenesis and neurite extension on inhibitory substrates. Results from completed microarray studies that have been confirmed by quantitative RT-PCR and Western blotting have determined that specific immune/inflammatory molecules such as chemokines and their receptors (e.g., CXCL12 and CXCR4) are elevated in TG mice following SCI during periods of oligogenesis/remyelination and functional recovery. With respect to our second objective we hypothesize that inhibiting astroglial- NF?B promotes an environment that is favorable for oligogenesis and remyelination. These hypotheses and our experimental objectives will be tested in the following specific aims.
Specific Aim 1 : Investigate the role of oxidative injury in astrocyte mediated oligodendrocyte death and demyelination.
Specific Aim 2 : Investigate the role of inflammation in astrocyte mediated oligodendrocyte death and demyelination.
Specific Aim 3 : Determine what effect inhibiting astroglial- NF?B has on oligogenesis and remyelination following SCI.
Specific Aim 4 : Investigate the role of CXCL12 and CXCR4 in oligogenesis and remyelination following SCI.

Public Health Relevance

Studies in this application will better define mechanisms of oligodendrocyte death and demyelination following spinal cord injury. In addition we will also investigate the role of astrocytes and secreted factors that may promote remyelination and oligodendrogenesis. Successful completion of these studies may lead to the development of therapies for spinal cord injury, multiple sclerosis and other neurodegenerative disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Jakeman, Lyn B
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Drexel University
Schools of Arts and Sciences
United States
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Mironets, Eugene; Osei-Owusu, Patrick; Bracchi-Ricard, Valerie et al. (2018) Soluble TNF? Signaling within the Spinal Cord Contributes to the Development of Autonomic Dysreflexia and Ensuing Vascular and Immune Dysfunction after Spinal Cord Injury. J Neurosci 38:4146-4162
Bernardes, Danielle; Brambilla, Roberta; Bracchi-Ricard, Valerie et al. (2016) Prior regular exercise improves clinical outcome and reduces demyelination and axonal injury in experimental autoimmune encephalomyelitis. J Neurochem 136 Suppl 1:63-73
Madsen, Pernille M; Motti, Dario; Karmally, Shaffiat et al. (2016) Oligodendroglial TNFR2 Mediates Membrane TNF-Dependent Repair in Experimental Autoimmune Encephalomyelitis by Promoting Oligodendrocyte Differentiation and Remyelination. J Neurosci 36:5128-43
Novrup, Hans G; Bracchi-Ricard, Valerie; Ellman, Ditte G et al. (2014) Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice. J Neuroinflammation 11:159
Dellarole, Anna; Morton, Paul; Brambilla, Roberta et al. (2014) Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling. Brain Behav Immun 41:65-81
Brambilla, Roberta; Morton, Paul D; Ashbaugh, Jessica Jopek et al. (2014) Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. Glia 62:452-67
Zha, Ji; Smith, Annalise; Andreansky, Samita et al. (2014) Chronic thoracic spinal cord injury impairs CD8+ T-cell function by up-regulating programmed cell death-1 expression. J Neuroinflammation 11:65
Johnstone, Joshua T; Morton, Paul D; Jayakumar, Arumugam R et al. (2013) Reduced extracellular zinc levels facilitate glutamate-mediated oligodendrocyte death after trauma. J Neurosci Res 91:828-37
Bigford, Gregory E; Bracchi-Ricard, Valerie C; Keane, Robert W et al. (2013) Neuroendocrine and cardiac metabolic dysfunction and NLRP3 inflammasome activation in adipose tissue and pancreas following chronic spinal cord injury in the mouse. ASN Neuro 5:243-55
Morton, Paul D; Dellarole, Anna; Theus, Michelle H et al. (2013) Activation of NF-*B in Schwann cells is dispensable for myelination in vivo. J Neurosci 33:9932-6

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