Gulf War Illness (GWI) is a poorly understood illnesses that has a broad impact on the body's communication and control systems (nervous and hormone systems) as well as its repair and defend functions (immune system). Traditional medical research looks for broken parts in these systems without paying much attention to how the parts fit together and whether or not the complete assembly is well tuned and operating at peak efficiency. In this proposal, we hope to continue our analysis of how poorly tuned the fight-or-flight survival response may have become in patients with GWI. In much the same way as pilots use simulators to understand the capabilities of their aircraft during flight training, we have been using a computer mock-up of the human body's fight-or-flight response to improve our understanding of GWI. Using simulations, we have begun to map the new characteristics of this altered survival response in sick Veterans. These have shown that the body's own control mechanisms may have been coerced into supporting continued illness in GWI and in doing so may also promote resistance to treatment. With knowledge of these altered control mechanisms in hand, we have used large computing platforms to develop general strategies to optimally use the endocrine and immune systems' new rules of play in order safely bring these back into their normal performance envelope. These first steps have indicated that combination treatments where immune function and hormone levels are both adjusted in a coordinated fashion produce much more promising outcomes than any single treatment administered alone.

Despite the complexity of our current computer models, we hope to further improve their level of realism not only to fine-tune these first treatment strategies but also most importantly to correct or avoid those that could have dangerous side effects. We will do this by improving our estimates of the time windows over which the body's basic control actions occur as well as by incorporating more detailed information about the properties of drugs that are already approved in clinic and that may be used effectively to treat GWI. In parallel with this proposal, our team has now been funded to validate these computer-based predictions using animals testing as well as by directly evaluating immune response in blood samples from afflicted Veterans. Finally, these simulations can be adjusted to mimic the response of a specific individual or group of individuals. Our model predictions so far have shown that men and women may respond quite differently to treatment. Our team has also been funded to map the illness profile of GWI in female Veterans, thereby making data available to support simulation of treatment in this population. As a key component of a larger research program, the current proposal promises to deliver much more realistic treatment designs that can now be directly validated through sister projects. Building on the important synergy between these efforts in computer-based screening and laboratory validation, it is our objective to a clear treatment strategy and significant body of evidence in support of human clinical trials based on a combination of medications already in clinic.