BLRD Research Career Scientist Award Application

Traumatic brain injury and other neurodegenerative disorders, e.g., Alzheimer’s Disease (AD), amyotrophic lateral sclerosis (Lou Gehrig’s disease, ALS), and related conditions, have an especially significant and increasing prevalence in the Veteran population. Gulf War illness has a high incidence among Veterans that served in the 1990-1991 Persian Gulf conflict and neurologic problems are common. It is essential that the underlying mechanisms that contribute to these conditions are understood so that treatments can be developed to improve the outcomes for Veterans and others. I have been studying the molecular genetic aspects of neurons and glia in the brain and spinal cord to determine how we can best modulate regulatory pathways to block and reverse neurodegenerative signaling that results in behavioral problems. In the course of these investigations, we examine human CNS samples obtained from brain banks, animal models, and model neurons in tissue culture. We evaluate gene expression changes and interactions that occur during the course of neurodegeneration in a variety of brain and spinal cord samples and model systems to compare alterations that are specific to the various disorders so that we can characterize factors that can be targeted to obtain neuroprotection and improved functional performance. I have determined key mechanisms responsible for central nervous system neurodegeneration. Areas of current discovery include Alzheimer's disease, important to the aging Veteran and general population, and traumatic brain injury which is becoming increasingly understood in terms of injury exposures in sports and importantly, is unfortunately the signature affliction of recently deployed military forces. In this arena I have, for example, identified therapeutic targets by defining neurodegenerative mechanisms and demonstrating that attacking these targets results in reduced activation of caspase- 3, improved neuroprotective gene expression in the brain, and reduced functional deficits, measured with behavioral and cognitive tests, by treatment after injury. We have found that several genes responsible for the loss of neuronal function are influenced significantly by a handful of inflammatory responsive regulatory factors that control the transcription rates, or gene expression, of the proteins important to neuronal health. For example, we found that inflammatory responsive regulatory transcription factors can be modulated to produce neuroprotective levels of intracellular proteins through selective upregulation and downregulation. By treating models with our intracellular, regulatory modulators, we have not only positively influenced biochemical pathways, we have demonstrated improved memory function in neurodegenerative conditions compared to untreated controls. We are currently extending this research to additional neurological problems that occur more frequently in Veterans and are seeking to advance beneficial therapeutic strategies.