There are a number of neurological disorders that result from perinatal brain damage. While there is no single cause of these disorders, there is a strong correlation between hypoxia-ischemia (H/I) and damage to the cerebral gray and white matter. Despite progress in understanding the pathogenesis of hypoxic-ischemic injury, we have an incomplete appreciation for the mechanisms leading to permanent brain injury and more importantly there is no clear explanation for the failure of regeneration. Increasingly, investigators are beginning to appreciate the impact of this injury on the subventricular zone (SVZ), which is that region of the immature brain that harbors the multipotential neural stem cells/progenitors (NSPs) that are endowed with the ability to generate neurons, astrocytes and oligodendrocytes. The specific goal of this proposal is to identify signals that induce the differentiation of glial precursors towards astrocytes and to evaluate recovery from H/I when specific astrocyte inducers are antagonized. Our preliminary data indicate that there is an increase in the production of astrocytes from SVZ cells at the expense of myelinating oligodendrocytes following recovery from perinatal H/I. Thus, our hypothesis is that as a result of injury-induced cytokines, that there is aberrant production of astrocytes from glial progenitors in the SVZ and that this glial dysgnesis contributes to the permanent deficit in white matter oligodendrocytes that occurs subsequent to H/I. Seminal studies on brain development have shown that neural precursors are responsive to extrinsic signals that govern their differentiation choices. We hypothesize that as a result of an H/I insult that specific signals are now present that would otherwise be absent.
The specific aims of this proposal are to: 1) Test the hypothesis that perinatal H/I increases the production of astrocytes from glial progenitors in the SVZ;2) Test the hypothesis that the damaged neonatal brain produces factors that promote astrocyte generatation from postnatal SVZ cells;3) Establish which transcription factors are active in postnatal SVZ cells by relevant astroglial inducers;and 4) Establish whether a pharmacological antagonist of the TGF-? receptor, ALK5, will prevent the aberrant production of astrocytes in vitro and in vivo after H/I. We anticipate that the knowledge obtained from these studies will lead to pharmacological interventions for infants surviving H/I or other disturbances of brain development to enable the infant brain to develop more normally. The insights we gain from our studies also will be applicable to a broad range of injuries and diseases of the CNS, as well as to studies where exogenous neural precursors will be transplanted into the brain, where excessive astroglial differentiation or astrogliosis are deemed undesirable.
Despite progress in understanding the pathogenesis of hypoxic-ischemic injury, we have an incomplete appreciation for the mechanisms leading to permanent brain injury and more importantly there is no clear explanation for the failure of regeneration. The specific goal of this proposal is to identify signals that induce the differentiation of neural precursors towards astrocytes and to evaluate recovery from H/I when specific astrocyte inducers are antagonized. The insights we gain from our studies also will be applicable to a broad range of injuries and diseases of the CNS, as well as to studies where exogenous neural precursors will be transplanted into the brain, where excessive astroglial differentiation or astrogliosis are deemed undesirable.
|Kim, Brian H; Guardia Clausi, Mariano; Frondelli, Michelle et al. (2017) Age-Dependent Effects of ALK5 Inhibition and Mechanism of Neuroprotection in Neonatal Hypoxic-Ischemic Brain Injury. Dev Neurosci 39:338-351|
|Sabo, Jennifer K; Heine, Vivi; Silbereis, John C et al. (2017) Olig1 is required for noggin-induced neonatal myelin repair. Ann Neurol 81:560-571|
|Felling, Ryan J; Covey, Matthew V; Wolujewicz, Paul et al. (2016) Astrocyte-produced leukemia inhibitory factor expands the neural stem/progenitor pool following perinatal hypoxia-ischemia. J Neurosci Res 94:1531-1545|
|Buono, Krista D; Goodus, Matthew T; Guardia Clausi, Mariano et al. (2015) Mechanisms of mouse neural precursor expansion after neonatal hypoxia-ischemia. J Neurosci 35:8855-65|
|Chen, Hongxin; Goodus, Matthew T; de Toledo, Sonia M et al. (2015) Ionizing Radiation Perturbs Cell Cycle Progression of Neural Precursors in the Subventricular Zone Without Affecting Their Long-Term Self-Renewal. ASN Neuro 7:|
|Moore, Lisamarie; Bain, Jennifer M; Loh, Ji Meng et al. (2014) PDGF-responsive progenitors persist in the subventricular zone across the lifespan. ASN Neuro 6:|
|Brazel, Christine Y; Alaythan, Abdulaziz A; Felling, Ryan J et al. (2014) Molecular features of neural stem cells enable their enrichment using pharmacological inhibitors of survival-promoting kinases. J Neurochem 128:376-90|
|Simonishvili, Sopio; Jain, Mohit Raja; Li, Hong et al. (2013) Identification of Bax-interacting proteins in oligodendrocyte progenitors during glutamate excitotoxicity and perinatal hypoxia-ischemia. ASN Neuro 5:e00131|
|Alagappan, Dhivyaa; Balan, Murugabaskar; Jiang, Yuhui et al. (2013) Egr-1 is a critical regulator of EGF-receptor-mediated expansion of subventricular zone neural stem cells and progenitors during recovery from hypoxia-hypoglycemia. ASN Neuro 5:183-93|
|Bain, Jennifer M; Moore, Lisamarie; Ren, Zhihua et al. (2013) Vascular endothelial growth factors A and C are induced in the SVZ following neonatal hypoxia-ischemia and exert different effects on neonatal glial progenitors. Transl Stroke Res 4:158-70|
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