This pilot GWI research project seeks to extend and validate our early findings of a potential role for telomere biology/telomerase disruption in GWI pathogenesis. We have previously developed and extensively characterized a mouse model of exposure to the Gulf War agents Pyridostigmine Bromide (PB) and Permethrin (PER) wherein the mice receive acute (10 days) exposure and have then been evaluated at a range of timepoints extending to 22 months post exposure (approximately 2 years of age). We consider that this model is relevant to the relatively acute exposure suffered by our troops in 1990/1991, and the development and persistence of symptomatology 25 years later. We observe neurobehavioral deficits and pathogenic biochemical and neuropathological changes in the brains and blood of these mice. Aging is a biological process that affects most cells, organisms and species, increasing susceptibility to many diseases including neurodegenerative diseases, cardiovascular disease and cancer. Telomere biology is now known to be a critical component of the aging and disease process, presenting telomere maintenance (through action of the telomerase enzyme) as a therapeutic target. Individuals with GWI suffer from a diverse array of chronic conditions, and we have hypothesized that their deployment related exposures may have caused a fundamental disruption of telomere biology homeostasis. Our pilot data from cell culture and our animal models suggest that there is disruption of telomerase activity following exposure to the GW agents PB and PER. Thus, the goal of this project is to further explore this phenomenon in blood samples from previously collected GW-agent-exposed and unexposed mouse cohorts, and to then evaluate the effects of treatment with telomerase maintaining/boosting compounds in new cohorts of GWI mice and controls. We appreciate that a possible role for telomere biology in GWI presents many areas for further investigation, including mechanism of action for how GW agents caused such disruption. However, given that our current GWI patient population suffered their toxic exposures 25 years ago, in this pilot project we wish to first validate telomere/telomerase disruption in our model, and then determine if this line of research holds any promise as a therapeutic strategy for veterans with GWI. If our hypothesis is upheld, then a future full scale Merit submission will explore the relationship between GW agent exposure and telomere biology in much greater detail, to hone therapeutic approaches.
Approximately 25% of the 700,000 US veterans who served in the 1990-1991 Gulf War are afflicted with Gulf War Illness (GWI) - a multisymptom presentation including central nervous system (CNS) based symptoms, such as cognitive deficits, inflammation and chronic pain. There are no effective treatments for GWI, and it is critical that we continue to explore mechanisms through which toxic exposures can evince such chronic effects. We have developed a mouse model that exhibits lifelong CNS dysfunction after exposure to agents known to have caused GWI. We now have preliminary data to support a role for disruption of telomere biology in this model, and so in this pilot application we propose further work to confirm and validate telomere maintenance as a target for therapeutic intervention in GWI.