The primary goal of this research is to elucidate the mechanism of Reovirus induced spinal cord injury and to identify effective strategies to improve disease outcome. Reovirus infection of the spinal cord includes infection of motor neurons and results in acute flaccid paralysis. Reovirus infection of the brain is reported to induce apoptosis of infected neurons and activate transcription factors. Currently, the mechanisms of Reovirus injury to the spinal cord are poorly defined. Injury due to Reovirus infection of the spinal cord will be evaluated by immunohistology and western blot for injury mechanisms in Aim 1. Analysis will include markers of apoptosis, oxidative stress, inflammation, and calpain activation.
In Aim 2, mechanistic differences between brain and spinal neuronal infection will be elucidated using apoptotic and DNA damage pathway specific oligo-gene arrays using RNA isolated from Laser Capture Microdissected neurons from infected and uninfected tissue. LCM will allow us to examine the reovirus induced transcriptional neuronal response from neurons within CNS tissue. Identification of the role of caspase proteases and oxidative stress, which are known to be up regulated in neurological injuries, will be examined further in reovirus spinal cord injury by treating mice with specific inhibitors of caspase and free radical scavengers in Aim 3. These treatments are expected to improve disease outcome of infected mice, as measured by decreases in injury mechanism markers and locomotor function.
This work will increase knowledge of the ways viruses interact with cells in the central nervous system (CNS). Improving the understanding of how viruses cause neurological disorders will allow advances in treatment design for illnesses caused by viral infection of the CNS. Some treatment options, outside antivirals, will be tested during the proposed work. ? ?
