Protracted oligodendrocyte (OL) death occurs after spinal cord injury (SCI). Because these cells myelinate axons, their loss leads to axon dysfunction and contributes to functional loss after SCI. Although many studies have characterized OL death after SCI, few have examined whether endogenous OL replacement occurs. We recently noted that a large number of new OLs are generated in the rim of tissue surrounding the lesion cavity after SCI. In the current proposal, these exciting findings will be followed up by determining if these new OLs contribute to axon remyelination and examining the mechanisms involved in their formation. Specifically, we will test the hypothesis that OL genesis in the traumatically injured adult spinal cord leads to remyelination of spinal axons and is dependent on astrocyte-derived CNTF.
In Aim 1, we will expand upon preliminary data by characterizing the spatio-temporal extent of OL remyelination after SCI. Because only newly generated OLs can remyelinate axons, this data will provide information on the extent that the new cells contribute to endogenous repair. To complement this data, we will use GFP-retroviral lineage tracing to examine the fate of dividing cells after injury and to fluorescently label newly derived OLs and myelin ensheathing axons. These studies will be followed up in Aim 2 by examining the extent to which new OL genesis and OL remyelination depend on the presence of CNTF after SCI. Lentiviral-siRNA technology will be used to silence CNTF expression and spinal cords will be examined for changes in oligodendrocyte progenitor proliferation, new OL formation and myelination. Based on our pilot data, we predict that the number of OLs along lesion borders will be significantly reduced thereby leading to a decrease in remyelination of spinal axons. We will also examine the functional consequences of the absence of CNTF and reduction on oligogenesis.
In Aim 3, we will examine the mechanisms of action for CNTF-mediated effects, including evaluating cellular expression of CNTF receptors and intracellular signaling molecules. Since CNTF is known to stimulate FGF-2 production and we and others show that FGF-2 is upregulated after SCI, we will also evaluate whether CNTF is essential for post-SCI FGF-2 expression. Collectively, the data generated will provide novel information on regulation of new OL formation in the injured adult CNS and the ability of these cells to help repair the damage induced by traumatic SCI.
of this proposal is that the data will shed light on how new cells are formed after injury to the spinal cord and whether the new cells can help repair the damage. By understanding what controls the new cell formation, we will gain an understanding of what the cells are capable of doing and how to manipulate the injury site to enhance their reparative abilities.
|Church, Jamie S; Kigerl, Kristina A; Lerch, Jessica K et al. (2016) TLR4 Deficiency Impairs Oligodendrocyte Formation in the Injured Spinal Cord. J Neurosci 36:6352-64|
|Hesp, Zoe C; Goldstein, Evan Z; Goldstein, Evan A et al. (2015) Chronic oligodendrogenesis and remyelination after spinal cord injury in mice and rats. J Neurosci 35:1274-90|
|Nielson, Jessica L; Guandique, Cristian F; Liu, Aiwen W et al. (2014) Development of a database for translational spinal cord injury research. J Neurotrauma 31:1789-99|
|Sahinkaya, F Rezan; Milich, Lindsay M; McTigue, Dana M (2014) Changes in NG2 cells and oligodendrocytes in a new model of intraspinal hemorrhage. Exp Neurol 255:113-26|
|Alexander, Jessica K; Cox, Gina M; Tian, Jin-Bin et al. (2012) Macrophage migration inhibitory factor (MIF) is essential for inflammatory and neuropathic pain and enhances pain in response to stress. Exp Neurol 236:351-62|
|Schonberg, David L; Goldstein, Evan Z; Sahinkaya, Fatma Rezan et al. (2012) Ferritin stimulates oligodendrocyte genesis in the adult spinal cord and can be transferred from macrophages to NG2 cells in vivo. J Neurosci 32:5374-84|
|Kigerl, Kristina A; Ankeny, Daniel P; Garg, Sanjay K et al. (2012) System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo. Exp Neurol 233:333-41|
|Almad, Akshata; Lash, A Todd; Wei, Ping et al. (2011) The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice. Exp Neurol 232:309-17|
|Gensel, John C; Schonberg, David L; Alexander, Jessica K et al. (2010) Semi-automated Sholl analysis for quantifying changes in growth and differentiation of neurons and glia. J Neurosci Methods 190:71-9|
|Almad, Akshata; McTigue, Dana M (2010) Chronic expression of PPAR-delta by oligodendrocyte lineage cells in the injured rat spinal cord. J Comp Neurol 518:785-99|
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