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.
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.
|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|
|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|
|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|
|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|
|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|
|Bracchi-Ricard, Valerie; Lambertsen, Kate L; Ricard, Jerome et al. (2013) Inhibition of astroglial NF-*B enhances oligodendrogenesis following spinal cord injury. J Neuroinflammation 10:92|
|Morton, Paul D; Johnstone, Joshua T; Ramos, Angel Y et al. (2012) Nuclear factor-*B activation in Schwann cells regulates regeneration and remyelination. Glia 60:639-50|
|Brambilla, Roberta; Ashbaugh, Jessica Jopek; Magliozzi, Roberta et al. (2011) Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain 134:2736-54|
|Zhang, Yan Ping; Fu, Eugene S; Sagen, Jacqueline et al. (2011) Glial NF-*B inhibition alters neuropeptide expression after sciatic nerve injury in mice. Brain Res 1385:38-46|
|Fu, Eugene S; Zhang, Yan Ping; Sagen, Jacqueline et al. (2010) Transgenic inhibition of glial NF-kappa B reduces pain behavior and inflammation after peripheral nerve injury. Pain 148:509-18|
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