Seven million Americans are presently incapacitated as a result of traumatic brain injury (TBI) with 500,000 new patients admitted each year. TBI is a devastating disability that leads to sensory and motor dysfunction, learning and memory impairment, and cognitive deficits. These defects result from, in part, tissue destruction and focal cell losses. Cell replacement strategies have been one approach to restoring brain function, and an alternative to cellular transplantation is stimulation of endogenous neurogenesis. We hypothesize that enhancement of neural stem/progenitor cell (NSPC) numbers through improved proliferation and survival will lead to tissue sparing and behavioral recovery. In acute TBI, this is likely through a mechanism where NSPCs/neuroblasts provide a trophic environment for tissue sparing. We hypothesize that ephrinB3 and its receptors, EphB3 and EphA4, provide a regulatory signal to subventricular zone (SVZ)-derived NSPCs, which limit proliferation, survival, and neuroblast migration to the site of injury.
Aim 1 of this grant will examine the role of ephrinB3 and its receptors on NSPC proliferation, survival, and neuroblast migration following cortical contusion impact (CCI) injury using transgenic mouse models and viral over-expression approaches.
Aim 2 will examine the specificity of SVZ-derived cells in recovery following CCI injury, and determine whether inhibiting p53 in NSPCs leads to enhance neurogenesis and functional recovery.
Aim 3 will examine whether Ephs regulate neuroblast migration through cell autonomous signaling and/or through vascular remodeling. Together, we believe our analysis will clearly address the protective role of the SVZ after TBI, and whether ephrinB3 and its receptors are critical regulators of neurogenesis and TBI recovery. Furthermore, we anticipate our findings will lead to therapeutic strategies to treat TBI patients.
The studies described in this proposal will examine the mechanisms that regulate adult neurogenesis following traumatic brain injury, and determine whether stimulating of this process can function to promote functional recovery.
|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|
|Nelersa, Claudiu M; Barreras, Henry; Runko, Erik et al. (2012) High-content analysis of proapoptotic EphA4 dependence receptor functions using small-molecule libraries. J Biomol Screen 17:785-95|
|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|
|del Valle, Kara; Theus, Michelle H; Bethea, John R et al. (2011) Neural progenitors proliferation is inhibited by EphB3 in the developing subventricular zone. Int J Dev Neurosci 29:9-14|
|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|
|Zhuang, Zhiye; Yang, Bing; Theus, Michelle H et al. (2010) EphrinBs regulate D-serine synthesis and release in astrocytes. J Neurosci 30:16015-24|
|Furne, Celine; Ricard, Jerome; Cabrera, Jorge Ruben et al. (2009) EphrinB3 is an anti-apoptotic ligand that inhibits the dependence receptor functions of EphA4 receptors during adult neurogenesis. Biochim Biophys Acta 1793:231-8|
|Yu, Tzong-Shiue; Zhang, Gui; Liebl, Daniel J et al. (2008) Traumatic brain injury-induced hippocampal neurogenesis requires activation of early nestin-expressing progenitors. J Neurosci 28:12901-12|
|Miles, Darryl K; Kernie, Steven G (2008) Hypoxic-ischemic brain injury activates early hippocampal stem/progenitor cells to replace vulnerable neuroblasts. Hippocampus 18:793-806|
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