Injury to the brain caused by cerebral ischemia is a major public health concern. Studies have determined that the brain damage associated with cerebral ischemia is mediated by over-stimulation of excitatory amino acid receptors, oxidative stress, as well as inflammatory factors. Our laboratory demonstrated - using an in vitro model of the ischemic penumbra - that astrocyte-mediated alterations in system xc- (cystine/glutamate antiporter) contribute to the development and progression of inflammatory (IL-12-mediated) hypoxic neuronal injury. Thus, we believe that system xc- has the potential to be a novel therapeutic target for stroke. However, to validate this hypothesis, our results must be confirmed in vivo. Mice harboring a natural loss of function mutation in the Slc7a11 (sut) gene - which encodes for xCT, the light chain dictating substrate specificity in system xc- - and xCT null mutant mice have been described in the literature. However, these are global knockouts. To date no tissue-specific knockout for this allele exists. Hence, the overall goal of this project is to develop (Aim 1) and characterize (Aim 2) an astrocyte-specific conditional knockout mouse of the Slc7a11 gene for the ultimate use in in vivo.

Public Health Relevance

Morbidity associated with cerebral ischemia (stroke) remains a huge emotional and economic burden due in large part to a void in treatment options to protect against secondary injury. It is our contention that successful completion of this application [i.e., the successful generation of a Scla711 (xCT) conditional knockout animal] will allow us to assess the viability of our hypothesis that astrocyte system xc- (cystine/glutamate transporter) is a novel therapeutic target in stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS074756-02
Application #
8302237
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (03))
Program Officer
Bosetti, Francesca
Project Start
2011-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$259,000
Indirect Cost
$84,000
Name
Syracuse University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
002257350
City
Syracuse
State
NY
Country
United States
Zip Code
13244