The Role of Astroglial-NF--kB in SCI

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): 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.