Elevated extracellular glutamate is known to play a central role in ischemic brain damage. The current proposal stems from key preliminary data demonstrating that induction of Glutamate Oxaloacetate Transaminase (iGOT) can metabolize extracellular glutamate ([Glu]o) via a truncated TCA cycle to sustain cell viability in the face of hypoglycemic challenge. Here, two strategies to achieve iGOT protection in the brain are employed. (1) Supplemental oxygen is used as a tool to study mechanisms of GOT induction. We propose that when supplemental oxygen is used to correct stroke-induced hypoxia while hypoglycemia remains, GOT metabolizes [Glu]o to serve as life-sustaining energy source for neural cells. (2) Biochanin A, a phytoestrogen isoflavone is investigated as a small molecule that induces GOT expression and protects against ischemic stroke injury in vivo. As a safe and natural dietary factor with an established track record of clinical testing for other indications (.e. cholesterol lowering), biochanin A represents a therapeutic target that can quickly be translated to clinical study. The following three specific aims will be addressed:
Aim 1 : Identify endogenous and therapeutic pathways of GOT induction in neural cells.
Aim 2 : In vivo functional spectroscopy to characterize the significance of iGOT in handling brain tissue Gly, corresponding ATP levels and lesion volume at the stroke-affected site.
Aim 3 : Determine the neuroprotective efficacy of iGOT targeting therapy. The focus of the proposal is to address a central hypothesis which is conceptually innovative in highlighting the significance of iGOT on [Glu]o metabolism during ischemic stroke.

Public Health Relevance

This proposal identifies therapeutic strategies to induce expression of an enzyme, Glutamate Oxaloacetate Transaminase (GOT), that can metabolize otherwise harmful glutamate at the site of ischemic brain injury. We hypothesize that GOT metabolism of glutamate protects neural cells from brain injury by two mechanisms: (1) reducing excitotoxic levels of extracellular glutamate caused by ischemic injury, (2) providing neurons an alternative source of energy in ischemic brain tissue challenged by hypoglycemia.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS085272-02
Application #
8729041
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Bosetti, Francesca
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210