Traumatic brain injury (TBI) is the most common type of acquired brain injury in both children and adults. To date, most of our insight into the pathology and treatment of TBI has focused on the regional physiology that occurs following trauma. Our knowledge about what happens at the cellular and molecular level following such injuries, however, is limited. Recently, endogenous neural stem cells have been implicated in the cellular remodeling that occurs following various types of brain injury. We recently demonstrated, using a mouse model of TBI, that neural stem cells proliferate, migrate to, and help remodel injured areas of the brain. It is still unclear, however, how much neural stem cells contribute to this remodeling and whether this contribution occurs in a functionally useful way. This proposal will focus on molecularly modeling TBI in the mouse hippocampus in order to determine the role of endogenous neural stem cells on hippocampal recovery after injury.
In Specific Aim 1, we will quantify the magnitude and time course of stem cell proliferation in the hippocampus following TBI. We will do this using a transgenic animal that we have developed and characterized that expresses GFP exclusively in adult neural progenitor cells.
In Specific Aim 2, we will determine whether functional recovery following TBI depends on hippocampal stem cell proliferation. We will do this using gain- and loss-of-function studies with mouse genetic models that we have recently developed. These include the nestin-rtTA-GFP mouse referenced above as well a Bax- deficient mouse that is neuroprotected following injury and has an abundance of neural stem cells. Finally, in Specific Aim 3, we will determine how intracellular calcium affects the survival of hippocampal neural stem cells. We will do this ex-vivo using organotypic hippocampal cultures and by measuring in individual neural stem cells how calcium flux is affected by cellular regulators such as the IP3 receptor. Acquired brain injuries, such as those resulting from trauma, are among the most common causes death and long-term disability in all age groups. It is unclear whether neural stem cells are responsible for some of the limited recovery that spontaneously occurs following such injuries. In this proposal, we will not only define the role that stem cells play in recovery following traumatic brain injury, but also identify how these cells might be manipulated to improve recovery after injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048192-05
Application #
7804486
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Owens, David F
Project Start
2006-07-15
Project End
2011-05-31
Budget Start
2010-05-01
Budget End
2011-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$305,619
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Cho, Kyung-Ok; Lybrand, Zane R; Ito, Naoki et al. (2015) Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun 6:6606
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
Sun, Chongran; Sun, Hui; Wu, Steven et al. (2013) Conditional ablation of neuroprogenitor cells in adult mice impedes recovery of poststroke cognitive function and reduces synaptic connectivity in the perforant pathway. J Neurosci 33:17314-25
Chen, Jian; Li, Yanjiao; Yu, Tzong-Shiue et al. (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:522-6
Gilley, Jennifer A; Yang, Cui-Ping; Kernie, Steven G (2011) Developmental profiling of postnatal dentate gyrus progenitors provides evidence for dynamic cell-autonomous regulation. Hippocampus 21:33-47
Blaiss, Cory A; Yu, Tzong-Shiue; Zhang, Gui et al. (2011) Temporally specified genetic ablation of neurogenesis impairs cognitive recovery after traumatic brain injury. J Neurosci 31:4906-16
Gilley, Jennifer A; Kernie, Steven G (2011) Excitatory amino acid transporter 2 and excitatory amino acid transporter 1 negatively regulate calcium-dependent proliferation of hippocampal neural progenitor cells and are persistently upregulated after injury. Eur J Neurosci 34:1712-23
Yang, Cui-Ping; Gilley, Jennifer A; Zhang, Gui et al. (2011) ApoE is required for maintenance of the dentate gyrus neural progenitor pool. Development 138:4351-62
Raman, Lakshmi; Kong, Xiangmei; Gilley, Jennifer A et al. (2011) Chronic hypoxia impairs murine hippocampal development and depletes the postnatal progenitor pool by attenuating mammalian target of rapamycin signaling. Pediatr Res 70:159-65
Kernie, Steven G; Parent, Jack M (2010) Forebrain neurogenesis after focal Ischemic and traumatic brain injury. Neurobiol Dis 37:267-74

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