This project involves the study of glutamic acid metabolism in synaptosomes. We will use 15N and 13C as metabolic tracers and gas chromatography-mass spectrometry as an analytic tool to answer these questions: i) How do neurons produce glutamate? Is glutamate the only precursor? Could alanine and the branched-chain amino acids be important N donors? Could 2-oxo-glutarate be an important C donor? ii) How is glutamate synthesis regulated? How is flux through the glutaminase pathway altered during depolarization? What is the effect of Ca2+? Of hypoglycemia? Of hypoxia? iii) How do synaptosomes metabolize glutamate? What is the role of oxidative deamination vs. transamination vs. the purine nucleotide cycle? How is this metabolism altered by hypoglycemia? By hypoxia? By depolarization? A unique feature of the work is our continued use of stable isotopes, particularly 15N, as a metabolic probe for brain nitrogen metabolism and of gas chromatography-mass spectrometry as an analytic tool for the determination of isotopic abundance. The information obtained from this work will provide a new perspective on the metabolism of glutamic acid, the most important excitatory neurotransmitter and the linchpin of all brain nitrogen metabolism. The data also may help us to understand the pathophysiology by which changes in glutamate synthesis and utilization may lead to the irreparable brain damage occurring consequent to anoxia and hypoglycemia, conditions in which glutamate excess is thought to be an important pathophysiologic factor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027889-02
Application #
3414325
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1991-09-30
Project End
1995-09-29
Budget Start
1992-09-30
Budget End
1993-09-29
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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