The 1990-1991 Gulf War (GW) conflict was relatively short and resulted in limited casualties. However, within months after their return, soldiers started reporting seemingly unrelated and unexplained symptoms. This illness was later classified as Gulf War Illness (GWI), which is now thought to affect 25% to 32% of the veterans who served our nation during the GW conflict. Now 22 years later, veterans with GWI continue to suffer from this illness, which remains untreatable due to the fact that chronic biological changes associated with GWI are not well understood. Given that a long time has elapsed since the original conflict, it is imperative that efforts are geared towards understanding the chronic disease features of GWI in order to develop appropriate treatments for GWI.
Since its inception a decade ago, the Roskamp Institute GWI Research Program has been dedicated to finding therapies that can target the chronic disease features of GWI. Pyridostigmine bromide (PB) and pesticides such as permethrin (PER) were chosen as GW agents in our animal modeling studies because a consensus was reached in 2008 (based on a report compiled by the Research Advisory Committee on GWI) that combined exposure to these agents was a key factor in the etiology of GWI. The team has developed several mouse models of exposure to GW agents that demonstrate neurobehavioral features, such as cognitive impairment and anxiety, that are similar to symptoms reported by veterans with GWI. In these mouse models, we observed an increase of astroglia staining (star-shaped brain cells that support and protect neurons) in exposed mice compared to controls. Having developed mouse models of GW agent exposure, the next step was to characterize and identify biological pathways, which can be targeted for developing therapies for veterans with GWI. Using proteomic technology that can examine several thousand proteins in a single experiment, we identified that the lipid metabolism, immune/inflammatory, and endocrine functions were affected at 5 and 16 months post-exposure in this mouse model. Given that lipid metabolism can influence the immune/inflammation and endocrine functions, targeting lipid metabolism may be a new approach by which several disease features of GWI may be improved. To better visualize the patterns of damage to the brain lipids after GW agent exposure, we developed a novel lipidomics assay that can examine several hundred lipids in one experiment. We found that choline-containing phospholipids (also known as lecithin), particularly those with ether bonds, were highly elevated in mouse models of GW agent exposure at 5 months post-exposure. We also found that levels of fatty acids were also higher in exposed animals compared to controls.
In this application, we will focus on testing three main strategies that are aimed at restoring homeostasis of these lipids in the brain. In one strategy, we will treat our GW agent-exposed mice with drugs that can reduce the production of choline-containing phospholipids. In another approach, we will use drugs that increase functional peroxisomes, which are small cellular bodies that synthesize ether lipids and cholesterol and break down very-long-chain fatty acids. In the last strategy, we will also supplement lipid metabolites (i.e., ketone bodies) as we expect that supplementation will enable astrocytes to deliver these to the neurons as an energy source to help with normal neuronal function and activity.
This proposal will address key areas of importance to the GWI Research Program (GWIRP), particularly one that is aimed at identifying therapies for treating GWI. Our approach, working with well-characterized mouse models of GW agent exposure using natural compounds or FDA-approved drugs as treatment targets, will minimize the risk of translational failures. This will ensure a better success rate in developing treatments for veterans with GWI. The Roskamp Institute scientists have been extremely successful in translational work, having already delivered a potential Alzheimer's disease treatment from laboratory to clinical trial testing. In addition, through our collaborations with GWI clinical researchers, we will be able to move these potential therapies forward for clinical testing once all the necessary regulatory approvals have been secured. Ultimately, these studies will identify novel therapies for treating GWI.