Proteomic Immune Profiling for the Therapeutic Modulation of Cognitive Impairment in a Novel GWI Mouse Model

Principal Investigator: AIT-GHEZALA, GHANIA
Institution Receiving Award: THE ROSKAMP INSTITUTE INC
Program: GWIRP
Proposal Number: GW100076
Award Number: W81XWH-11-1-0465
Funding Mechanism: Investigator-Initiated Research Award
Partnering Awards:
Award Amount: $925,368.00


Veterans of the Gulf War (1990-1991) have a higher rate of "chronic multi-symptom health problems" than either non-deployed military personnel or those deployed to other regions. The severity of illness can range from moderate effects (some problems, but ability to maintain a normal lifestyle) to highly debilitating, where it interferes with the activities of daily living. Nearly 20 years since the original conflict, most veterans with this illness continue to suffer from these chronic symptoms and only a few have either recovered or improved. Among the 37 persistent symptoms, the most commonly reported symptoms included fatigue, gastrointestinal problems, chronic and widespread pain, and neurological and musculoskeletal symptoms. Further investigations have revealed that symptoms relating to gastrointestinal, respiratory, and mood/cognition are the three key correlated symptoms reported to be present among both the UK and US Gulf War veterans. Additional support for significant cognitive component to Gulf War illnesses (GWI) comes largely from brain imaging studies showing damage to brain structures.

The cause of these central nervous system (CNS) abnormalities remains unknown. Interestingly, several clinical studies on GWI suggest that there is a significant impairment of immune and inflammatory responses in the periphery of veterans with GWI. Interestingly, the chemicals pyridostigmine bromide given to soldiers as prophylaxis against nerve gas attack and permethrin, a pesticide used to protect against pest-borne illnesses, have been shown to affect immune system and inflammation in animals. We suspect that these chemicals, in combination with each other, may have resulted in an increase of proinflammatory proteins, which could have subsequently entered the brain and caused clinical symptoms that we observe in veterans with GWI. Therefore, our work will focus on identifying biological functions in order to figure out the relationship between cognitive and the immune component of GWI. However, given the complexity of clinical presentation, which is probably obscured by the heterogeneity of the veteran population, due to hereditary and other environmental differences, the standard technical approaches may not be suitable for examining the underlying etiology of this illness. We have state-of-the- art technology available to address this problem as well as several decades of experience in researching brain inflammation associated with cognitive diseases. This "proteomic technology" is a method that enables us to identify and measure hundreds to thousands of proteins simultaneously even in a small amount of sample and therefore can provide a picture of several biological pathways at the same time. Therefore, we propose to use this technology to identify profiles that are specific to immune and inflammatory responses in a mouse model of GWI, thereby allowing us to examine the relationship between these GWI exposures and immune/inflammatory dysfunction in a more homogenous study sample. We will identify biological pathways that can be targeted using pharmacological approaches and other genetic animal modeling approaches. We will examine whether we can successfully target the immune/inflammatory component of GWI and whether by doing so we can resolve the brain inflammation and change neurobehavioral symptoms of cognitive impairment. We are confident that our approach here will potentially lead to several new therapeutic avenues for treatment of the brain inflammation component of GWI, ultimately leading to their clinical testing in veterans with this chronic and persistent sickness.