Progress to treat white matter injury (WMI) in preterm neonates has been hampered by fundamental gaps in the molecular mechanisms of remyelination failure. We seek to promote myelin regeneration by disrupting hyaluronic acid (HA)-mediated signaling that prevents white matter repair and functional plasticity. HA is processed by CNS hyaluronidases to HA fragments (HAf) of varying size. We found that a HAf of ~210 kDa inhibits oligodendrocyte progenitor cell (OPC) maturation in vitro and blocks myelination in vivo. The 210HAf promotes an OPC niche at the expense of myelination by utilizing an AKT-FoxO3 signaling pathway that constrains OPC differentiation. It is our unifying hypothesis that 210HAf blocks myelination through three complementary mechanisms that stimulate OPC proliferation, block preOL maturation and bias microglia to release ?anti-inflammatory? factors that constrain OPC differentiation. We will integrate genetic, cellular, and biochemical approaches using a neonatal rat model of hypoxia-ischemia, transgenic mice, primary OPCs and forebrain slice cultures.
In aim 1, we will determine a novel CNS role for the tumor suppressor Merlin that regulates OPC proliferation via 210HAf. We will define a pathway downstream of Merlin that promotes OPC proliferation via activation of epidermal growth factor receptor.
In aim 2, we found that 210HAf stimulates microglia to release factors associated with ?anti- inflammatory? states. We hypothesize that 210HAf promotes microglial release of these factors to disrupt white matter repair by constraining OPC differentiation. We will determine the expression of microglial cytokines stimulated by 210HAf and the HA receptors and signaling pathways involved that may promote an OPC niche. At the conclusion of aim 2, we will undertake in vivo studies to test a broad-spectrum hyaluronidase inhibitor, VCPAL that we have shown promotes myelination after adult WMI. We will determine if VCPAL shifts the balance from factors that promote OPCs toward a state that drives OPC maturation to oligodendrocytes.
In aim 3, we will define down-stream targets of the AKT-regulated transcription factor FoxO3 that is chronically activated by 210HAf to constrain OPC maturation. We will define novel mechanisms through which FoxO3 interacts with the chromatin remodeling factor Brg1, which we recently showed regulates OPC specification and differentiation by controlling expression of genes involved in early oligodendrocyte differentiation, like Olig2. We will also define the role of FoxO3 as a molecular marker of human myelination failure to define the window and response to interventions to promote OPC maturation. Our long-term objective is to define molecular mechanisms through which 210HAf signals to regulate WM inflammation and the balance between OPC survival, proliferation and differentiation. A detailed molecular understanding of these closely related processes will provide critically needed insights to develop new strategies to promote myelination.
This proposal focuses on recently discovered cellular and molecular mechanisms of disrupted regeneration and repair of neonatal white matter injury that prevent the normal maturation of the preterm developing human brain. We will employ pioneering molecular and histopathological approaches to define how two key cell types (oligodendrocyte progenitors and microglia) contribute to aberrant brain recovery (remyelination failure) after white matter injury. Our long-term goals are to develop novel therapies to promote enhanced myelination of chronic white matter lesions and develop a novel molecular marker (FoxO3) to identify the optimal time window after injury to institute therapies to enhance motor and neurobehavioral recovery for survivors of preterm birth.
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|Sherman, Larry S; Back, Stephen A (2017) Comment on: PH20 is not expressed in murine CNS and oligodendrocyte precursor cells. Ann Clin Transl Neurol 4:608-609|
|McClendon, Evelyn; Shaver, Daniel C; Degener-O'Brien, Kiera et al. (2017) Transient Hypoxemia Chronically Disrupts Maturation of Preterm Fetal Ovine Subplate Neuron Arborization and Activity. J Neurosci 37:11912-11929|
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|McNeal, David W; Brandner, Dieter D; Gong, Xi et al. (2016) Unbiased Stereological Analysis of Reactive Astrogliosis to Estimate Age-Associated Cerebral White Matter Injury. J Neuropathol Exp Neurol 75:539-54|
|Sherman, Larry S; Matsumoto, Steven; Su, Weiping et al. (2015) Hyaluronan Synthesis, Catabolism, and Signaling in Neurodegenerative Diseases. Int J Cell Biol 2015:368584|
|Back, Stephen A (2015) Brain Injury in the Preterm Infant: New Horizons for Pathogenesis and Prevention. Pediatr Neurol 53:185-92|
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