Approximately 1.4 million Americans sustain traumatic brain injuries (TBI) each year resulting in death or long-term disability. The use of stem cells to repair or replace damaged brain tissue is a new and exciting avenue of research. Although endogenous adult neural stem cells residing in the subventricular zone (SVZ) may be sequestered for repair and recovery after TBI, the exact mechanism underlying this process is not well understood. We have recently established that there is an early neurogenic response (i.e. proliferation, survival and migration) in the adult mouse SVZ following TBI. The neurogenic response is amplified in the absence of ephrinB3 and EphB3 receptor, which correlates with improved motor function. Based on these preliminary findings, the objective of this proposal is to examine whether ephrinB3 and its receptors are modified in response to brain injury and how their regional expression may influence homeostasis in the SVZ as well as migration and survival of SVZ-derived NPCs in the injured environment. Disruption of ephrin/Eph receptor interactions has been shown to profoundly alter neurogenesis (i.e. proliferation, migration and survival) in the naive SVZ. We hypothesize that down-regulation of ephrinBS and/or its receptor(s) in the SVZ promotes post-injury neurogenesis in response to moderate cortical damage and that this response is necessary for locomotor recovery after TBI.
Aim 1 of this application will first evaluate whether the relative expression levels of ephrinB3 and its receptor(s) are modified in the mouse forebrain following TBI by employing Western blot analysis, RNase protection assay and immunohistological techniques.
Aim 2 will examine the role of ephrinB3 and its receptor(s) in regulating proliferation, survival and migration in the SVZ and injured cortex using gain- and loss-of-function studies in a mouse model of TBI. Studies in Aim 3 will determine whether recovery of motor function after TBI depends on the recruitment and mobilization of SVZ-derived NPCs. There is great interest in exploiting resident neural stem cells for CNS regeneration. Studies outlined in this proposal will further enhance our understanding of the processes regulating neurogenesis in the injured and non-injured brain.
It is estimated that over a lifetime, it will cost between $600,000 and $1,875,000 to care for a survivor of severe TBI. The current studies seek to understand the mechanisms that govern a unique endogenous repair response to brain injury and to determine its role in long-term functional recovery. Our ultimate goal is to devise novel experimental therapies to treat brain injury and improve recovery of function in patients who sustain head trauma using adult neural stem cells.
|Okyere, Benjamin; Creasey, Miranda; Lebovitz, Yeonwoo et al. (2018) Temporal remodeling of pial collaterals and functional deficits in a murine model of ischemic stroke. J Neurosci Methods 293:86-96|
|Dixon, Kirsty J; Theus, Michelle H; Nelersa, Claudiu M et al. (2015) Endogenous neural stem/progenitor cells stabilize the cortical microenvironment after traumatic brain injury. J Neurotrauma 32:753-64|
|Theus, M H; Ricard, J; Glass, S J et al. (2014) EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury. Cell Death Dis 5:e1207|
|Baumann, Gisela; Travieso, Lissette; Liebl, Daniel J et al. (2013) Pronounced hypoxia in the subventricular zone following traumatic brain injury and the neural stem/progenitor cell response. Exp Biol Med (Maywood) 238:830-41|
|Theus, Michelle H; Ricard, Jerome; Liebl, Daniel J (2012) Reproducible expansion and characterization of mouse neural stem/progenitor cells in adherent cultures derived from the adult subventricular zone. Curr Protoc Stem Cell Biol Chapter 2:Unit 2D.8|
|Theus, Michelle H; Ricard, Jerome; Bethea, John R et al. (2010) EphB3 limits the expansion of neural progenitor cells in the subventricular zone by regulating p53 during homeostasis and following traumatic brain injury. Stem Cells 28:1231-42|