Glutamate is the major excitatory neurotransmitter in the human brain and is indispensable for normal neuronal signaling. However, under conditions of energy failure, for example following a stroke, uncontrolled release of glutamate can cause """"""""excitotoxic"""""""" death of neurons. Glutamate toxicity may be more commonly associated with diseases of the nervous system. Indeed, recent studies surprisingly demonstrated that astrocyte-derived primary brain tumors (gliomas) release large quantities of glutamate into the peritumoral space and led to the hypothesis that this glutamate release may purposely kill neurons thereby vacating space for invading tumor cells. In this proposal we are pursuing an alternate hypothesis. We hypothesize that glutamate release from glioma cells is an obligatory byproduct of cystine uptake into glioma cells via system Xc, a cystine-glutamate exchanger. Cystine uptake is essential for the production of glutathione (GSH) to maintain the cells redox status. Impairment of cystine uptake depletes GSH leading to growth arrest due to loss of defense against reactive oxygen species. Furthermore, glutamate released in the process not only causes excitotoxic pertiumoral neuronal loss but causes the autocrine/paracrine activation of AMPA receptors that promote glioma cell invasion. This proposal seeks to characterize the glutamate release/cystine uptake pathway(s) utilized by glioma cells with the objective to suppress tumor growth and invasion by inhibiting these transporters. The proposed studies range from a cellular and molecular identification of the underlying amino acid transporters and their role in tumor biology to the preclinical evaluation of drugs that specifically interfere with these transporters in animal models of the disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052634-03
Application #
7276792
Study Section
Special Emphasis Panel (ZRG1-MDCN-F (02))
Program Officer
Fountain, Jane W
Project Start
2005-08-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$319,033
Indirect Cost
Name
University of Alabama Birmingham
Department
Neurosciences
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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