Ionizing irradiation is commonly used in the management of malignant brain tumors. Although effective in many cases, therapeutic irradiation of the brain can cause significant normal tissue damage. In general, overt tissue injury occurs after relatively high doses, but less severe injury can occur after lower doses, which can lead to cognitive impairment. The pathogenesis of radiation-induced cognitive impairment is not clear but may involve neural subgranular zone (SGZ) precursor cells in the dentate gyrus of the hippocampus. These cells participate in the process or neurogenesis, continually producing cells that are able to migrate away and differentiate into mature dentate granule cells. Loss of dentate granule cells and/or proliferating precursor cells is associated with specific types of cognitive dysfunction. We have shown that neural precursor cells in the SGZ are exquisitely sensitive to irradiation, undergoing apoptosis after clinically relevant doses. Furthermore, we have shown that after irradiation there is a prolonged reduction in overall cell proliferation in the SGZ and a dose-related decrease in the production of new neurons. Lastly, we have data suggesting that oxidative stress may be involved in radiation-induced changes in the SGZ and in hippocampal precursor cell cultures. It is our contention that oxidative stress plays a critical role in the acute radiation response of proliferating neural precursors and in later reductions in hippocampal neurogenesis. Further we assert that inhibition of neurogenesis will lead to cognitive impairment. It is our overall objective to determine how oxidative stress affects the radiation response of SGZ precursor cells and their progeny and to identify compounds/strategies that will enable us to ameliorate the adverse effects of irradiation on hippocampal neurogenesis and cognitive function. We have defined 4 specific aims to address our objective: 1) Quantify the relationship between deficiencies in site-specific superoxide dismutases (SODs) and acute, radiation induced effects on proliferating SGZ precursor cells and their progeny; 2) Establish the relationship between site-specific SODs and hippocampal neurogenesis 2-6 months following-x-irradiation; 3) Quantify the ability of antioxidant SOD/catalase mimetic treatment to reduce SGZ apoptosis and to ameliorate radiation-induced inhibition of neurogenesis; and 4) Determine whether SOD mimetic treatment results in improved cognitive function in mice treated with x-rays.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS046051-01A1
Application #
6730449
Study Section
Radiation Study Section (RAD)
Program Officer
Owens, David F
Project Start
2003-12-01
Project End
2007-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$350,344
Indirect Cost
Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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