This application focuses on investigating signals in the subventricular zone (SVZ) that regulate oligodendrocyte (OL) development in the healthy and injured brain. OLs arise from neural stem cells in the SVZ and produce the myelin sheaths that insulate neuronal axons, thus allowing proper synaptic transmission. Damage to or loss of OLs results in many neurological problems, as can be seen in multiple sclerosis and other neurodegenerative diseases. Therefore, identifying endogenous mechanisms that regulate OL development and repair in vivo may lead to new therapeutic targets for treating such conditions. Our previous studies found that the signaling peptide, Endothelin-1, delays OL maturation after demyelination of white matter in the rodent brain. This suggests that Endothelin-1 is a novel regulator of OL development in vivo. To test this hypothesis, the function of Endothelin-1 in the SVZ during normal development and after white matter injury will be determined. First, the mechanism of Endothelin-1 in the postnatal SVZ will be genetically dissected using conditional knockout mice and RNA sequencing. Then, using the lysolecithin model of demyelination and viral tracing, the role of SVZ-derived Endothelin-1 in OL regeneration will be defined.
Damage to or loss of oligodendrocytes occurs in a wide range of neurodegenerative conditions, including demyelinating diseases such as multiple sclerosis and many central nervous system pathologies. Understanding the signaling pathways that regulate oligodendrocyte regeneration from endogenous oligodendrocyte progenitor cells in the brain may lead to new therapeutic strategies for treating such diseases. This study proposes to investigate the role of a signaling peptide, Endothelin-1 in oligodendrocyte development and regeneration in the subventricular zone with the hope of identifying a new pathway for therapeutic targeting.
| Adams, Katrina L; Gallo, Vittorio (2018) The diversity and disparity of the glial scar. Nat Neurosci 21:9-15 |
