Current Research Projects
 
Radiation and Oxidative Stress: Effects on Neurogenesis (NIH)
Principal Investigator: John R. Fike PhD
Co-Investigators: Charles L. Limoli PhD; Ting-Ting Huang PhD; Jacob Raber PhD
 
Radiation therapy is commonly used in the treatment of malignant brain tumors but can induce serious damage to normal tissues. A better understanding of the pathogenesis or development of normal tissue radiation injury could facilitate strategies to protect normal brain and lead to more effective radiation treatment in brain tumor patients. One serious adverse effect of radiation injury is cognitive impairment, the pathogenesis of which is unclear. However, data from our lab suggests that neural precursors in the dentate subgranular zone (SGZ) of the hippocampus may be involved. Furthermore we have shown that oxidative stress may be involved in the radiation changes observed in the SGZ. This project is designed 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. Both in vitro and in vivo models will be used, and quantitative measurements of neurogenesis will be made using immunohistochemistry and confocal microscopy.
 
Progressive Alterations of Central Nervous System Structure and Function are Caused by Charged Particle Radiation (NASA)
Principal Investigator: Gregory Nelson, PhD
Associate Director: John R. Fike PhD
Co-Investigators: John Archambeau MD; Polly Chang PhD; Michael Pecaut PhD
 
This project provides a comprehensive assessment of the effects of charged particle irradiation on the mammalian brain. The program encompasses 3 hypotheses, the first of which is administered by Dr. Fike. In this part of the program a series of in vivo studies will be done to determine the effects of charged particle irradiation on: 1) hippocampal neurons and microvessel endothelial cells; 2) neurogenesis in the dentate SGZ; 3) how levels of inflammatory cytokines changes as a function of radiation dose, (linear energy transfer (LET) and time after irradiation; and 4) mutational frequency in cells from the mouse hippocampus.
 
Inflammation in the Brain After Particulate Irradiation Predisposes the Hippocampus to a Heightened Vulnerability After a Secondary Insult (NASA)
Principal Investigator: John R. Fike
Co-Investigators: Linda J. Noble PhD; Andre Obenaus PhD; Nalin Gupta MD, PhD
 
A unique feature of the space radiation environment is the presence of high-energy charged particles including protons and iron ions. These particles may pose a significant hazard to space flight crews not only during the mission, but also later on Earth, when slow-developing adverse effects finally become apparent. Previous work in our lab has shown that iron ions significantly affect the cells in the dentate SGZ of the hippocampus that may be associated with specific cognitive functions. Furthermore, these changes are accompanied by a persistent inflammatory response, even after low radiation doses. We hypothesize that this persistent inflammation may predispose the brain to additional and more significant damage upon a secondary insult, in particular, mild to moderate traumatic brain injury (TBI). This study will involve irradiating mice with iron particles or protons, followed some time later by TBI. Changes in the cellular make-up of the SGZ and determination of the fate of newly born cells (i.e. neurogenesis) will be made using immunohistochemistry and confocal microscopy.
 
Effects of Low-Level Radiation Exposure on Neurogenesis and Cognitive Function: Mechanisms and Prevention (Department of Defense)
Principal Investigator: John R. Fike PhD
Co-Investigators: Charles L. Limoli PhD; Jacob Raber PhD
 
Radiation exposure does not have to be lethal to have significant consequences. The depletion of neural stem cells, for instance, could lead to prolonged effects in some tissues, particularly if those cells have limited regenerative potential. Because of the role the hippocampal neural precursor cells in the development and maintenance of memory, we hypothesize that these cells are a critical target in the radiation-induced impairment of cognitive function. We further contend that radiation effects on neurogenesis are mediated through oxidative stress and that, by reducing oxidative injury, we can ameliorate radiation-induced cognitive impairment. After treating mice with fractionated doses of X rays, we will quantify changes in neurogenesis and cognitive function. Then we will test the ability of specific antioxidant compounds to reduce those effects.
 
Neurogenesis and Traumatic Brain Injury in the Mouse (UC Neurotrauma Initiative)
Principal Investigator: John R. Fike PhD
Co-Investigator: Linda J. Noble PhD
 
Traumatic brain injury (TBI) in humans and animals results in a series of well-defined pathophysiological effects. In addition to specific structural changes, TBI induces significant cognitive impairment. Although data exist regarding the sequence of events in the development of TBI, there are uncertainties about specific cellular elements involved in structural and functional recovery after brain injury. We suggest, on one hand, that TBI will result in decreased neurogenesis within hippocampus, and that that decrease will be associated with resulting cognitive impairment. On the other hand, we believe that after TBI there will be increased neurogenesis in the subependyma, and that increase may be involved in structural/functional recovery near the lesion and at more distant sites. We hypothesize that changes in neurogenesis resulting from TBI will play important roles in the subsequent adverse effects or recovery after injury. We will use a well-established model of TBI to determine how focal TBI affects neurogenesis in the hippocampus and subependyma of the mouse, and to show that the magnitude of change, in terms of neurogenesis, is dependent upon the severity of injury.
 
Mechanisms of High LET Radiation Induced Genomic Instability in the CNS (NASA)
Principal Investigator: Charles L. Limoli PhD
Co-Investigator: John R. Fike PhD
 
This project will involve a series of in vitro studies to test the overall hypothesis that alterations in cellular redox state promote genomic instability that can adversely impact the CNS upon exposure to high LET irradiation.
 
Genomic Instability and Redox: Radioresponse of Brain Tumor Precursor Cells (ACS)
Principal Investigator: Charles L. Limoli, PhD
Co-Investigator: John R. Fike PhD
 
The goal of this in vitro project in to determine if changes in the cellular redox state promote genomic instability and altered radiosensitivity.
 
Neural Stem Cell and Brain Plasticity After Stroke
Principal Investigator: Jialing Liu PhD
Co-Investigators: John R. Fike PhD; Jacob Raber PhD
 
This project is a subcontract to a grant awarded to Dr. Liu to determine if disruption of dentate neurogenesis by irradiation will result in impaired structural and functional recovery after focal ischemic injury.