Effects of Microgravity and Full Spectrum Space Radiation on Neurons
Principal Investigator: Dr. Amy Bishop
University of Alabama in Huntsville
Nitric oxide (NO) is a free radical that is utilized by the CNS for normal physiological functions. However, when released in inappropriate locations, or in excess, NO results in the formation of nitrotyrosine, a marker for NO-mediated damage, and massive cell death. Cell death and nitrotyrosine formation are seen in spinal cord injury, neurodegenerative diseases, and damage such as that encountered by astronauts during space travel. Motor neuron cells pretreated with sub-toxic doses of NO gain significant resistance to normally toxic doses of NO, a phenomenon we termed induced adaptive resistance (IAR). Furthermore, when exposed to toxic doses of NO, adapted cells have little to no nitrotyrosine formation. IAR is dependent on the heme metabolizing enzyme, heme oxygenase 1 (HO-1). The overall aim is to elucidate and dissect the IAR phenomenon and by so doing, begin to understand native resistance mechanisms in the CNS that can be utilized to protect neurons against NO-mediated damage seen in CNS injury, neurodegenerative disease, and damage as seen in the microgravity of space travel. Specific aims:
1. To determine whether NO-induced cell death from space travel is due to the associated nitration of cellular proteins. If so then a) blocking 3NY formation should also block killing by NO and b) the nitration of cellular proteins, in the absence of NO treatment, should be sufficient to kill cells.
2. To determine if and how HO1 induces adaptive resistance from damage. Potentially, HO1 may induce adaptive resistance to NO by a.) lowering intracellular concentration of heme, b.) the generation of heme metabolites such as bilirubin and carbon monoxide, c) the combination of these actions, d) or by some other unknown activity associated with HO1.
3. To determine whether continuous exposure to low levels of NO will give continuous resistance to cellular damage acquired during space flight. An investigation of whether the window of IAR can be expanded has obvious therapeutic implications for astronauts.