Abstract

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.

Public Health Relevance

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049545-09
Application #
8606255
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Lavaute, Timothy M
Project Start
2004-07-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
University of Miami School of Medicine
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
City
Coral Gables
State
FL
Country
United States
Zip Code
33146

  Publications

Assis-Nascimento, Poincyane; Tsenkina, Yanina; Liebl, Daniel J (2018) EphB3 signaling induces cortical endothelial cell death and disrupts the blood-brain barrier after traumatic brain injury. Cell Death Dis 9:7
Dixon, Kirsty J; Turbic, Alisa; Turnley, Ann M et al. (2017) Explant Methodology for Analyzing Neuroblast Migration. Bio Protoc 7:
Dixon, Kirsty J; Mier, Jose; Gajavelli, Shyam et al. (2016) EphrinB3 restricts endogenous neural stem cell migration after traumatic brain injury. Stem Cell Res 17:504-513
Assis-Nascimento, Poincyane; Umland, Oliver; Cepero, Maria L et al. (2016) A flow cytometric approach to analyzing mature and progenitor endothelial cells following traumatic brain injury. J Neurosci Methods 263:57-67
Perez, Enmanuel J; Cepero, Maria L; Perez, Sebastian U et al. (2016) EphB3 signaling propagates synaptic dysfunction in the traumatic injured brain. Neurobiol Dis 94:73-84
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
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

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