Hypoglycemia is a common complication in the management of diabetes. Severe hypoglycemia can cause seizures, unconsciousness, and irreversible cognitive impairment, presumably because of neuronal injury and death. Astrocytes, the star-shaped glial cells found throughout the brain, perform important roles to support and protect neurons. Recent work indicates that in hypoglycemia, astrocytes are capable of rapidly generating substrates to feed energy-depleted neurons, probably by breakdown of intracellular glycogen. The mechanisms by which astrocytes sense dropping glucose levels, and the downstream signaling pathways controlling glycogen metabolism, are poorly understood. We propose a discovery-based, but focused approach to identify components of astrocytic hypoglycemic signaling pathways, utilizing two powerful and complementary methodologies: proteomics and a novel method of expression cloning. We will test a general hypothesis: Astrocytes possess specialized glucose signaling molecules and mechanisms enabling rapid regulation of substrates for neuronal metabolism in hypoglycemia.
The specific aims of the project are: 1) Identify molecular targets of acute, subacute and episodic hypoglycemia in astrocytes using two independent and complementary approaches: a) proteomics (two-dimensional gel electrophoresis with protein identification by mass spectrometry); and b) FIMS, a novel expression cloning method developed in our laboratory. 2) Validate targets using cell culture and in vivo models of hypoglycemia. The entire set of identified hypoglycemia-regulated proteins will be made available as a database for the research community. A subset of the targets identified will be the subject of future hypothesis-driven research projects in our laboratory. The longterm goal is to develop pharmacologic or molecular methods to augment or modulate neuroprotective aspects of the astrocytic response to hypoglycemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS045300-02
Application #
6667268
Study Section
Special Emphasis Panel (ZNS1-SRB-A (03))
Program Officer
Jacobs, Tom P
Project Start
2002-09-30
Project End
2004-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$185,000
Indirect Cost
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904