Biomedical Sciences Graduate Program | University of California, San Francisco

In the management of malignant brain tumors, radiotherapy is the single most effective treatment after surgical resection, but the radiation dose that can be used is limited by the tolerance of normal brain. Although overt tissue injury occurs after relatively high radiation doses, less severe injury can also occur which can lead to cognitive impairment. While the pathogenesis of radiation-induced cognitive dysfunction is not clear we feel it involves neural precursor cells in the dentate gyrus of the hippocampus. These precursor cells produce progeny that migrate away and differentiate into neurons, which become functionally integrated into the dentate gyrus. Depletion of these proliferating precursor cells leads to specific cognitive deficits. We have shown that neural precursor cells in the subgranular zone (SGZ) of the dentate gyrus are exquisitely sensitive to irradiation, undergoing apoptosis after clinically relevant doses. As a result, there is a prolonged reduction in overall cell proliferation in the SGZ and a dose-dependent decrease in the production of new neurons. We have data suggesting that oxidative stress and/or inflammatory processes may be involved in radiation-induced changes in the SGZ. It is our overall objective to determine how oxidative stress/inflammation 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.

Currently, the studies in my laboratory involve both in vivo and in vitro models which enable us to ask mechanistic and clinically relevant questions. Part of our strategy involves the use of knockout and transgenic mice so that we can determine if specific gene products are associated with the changes we observe after irradiation. For instance we are using mice deficient in the various superoxide dismutase (SOD) enzymes, or deficient in the specific chemokine receptors (CCR2) to address how those deficiencies affect acute responses and neurogenesis in the dentate SGZ. To complement these studies we are extracting precursor cells from the SGZ of the various knockout or overexpressing transgenic mice and maintaining them in culture for specific mechanistic studies.

Using these models, we are actively pursuing approaches to ameliorate radiation effects on SGZ neurogenesis. Using SOD/catalase mimetic drugs, or anti-apoptotic agents, we are determining if we can reduce acute apoptosis as well as later developing effects on neurogenesis. We are not only measuring the cellular responses in the SGZ but are also correlating changes in precursor cell loss with subsequent cognitive impairment as measured by a battery of neurobehavioral tests. Our studies of the molecular, cellular and behavioral mechanisms associated with cranial irradiation will not only increase our knowledge of the neurobiology of the SGZ, but will hopefully lead to a better understanding of radiation injury and lead to new strategies to combat this clinically-significant problem.

Selected Publications