Mitochondrial Dysfunction and Aberrant Immune Activation in the Pathobiology of Gulf War Illness
Abstract
Approximately 25% to 32% of the nearly 700,000 Veterans who served in the 1991 Persian Gulf War developed a currently untreatable disorder known as Gulf War Illness (GWI). GWI is characterized by multiple symptoms, including fatigue, headaches, widespread musculoskeletal pain, and various central nervous system impairments, such as learning and memory deficits, depression, anxiety, inability to concentrate, and sleep irregularities. The exact cause of GWI is unknown, although a prevailing hypothesis suggests that chemical exposures experienced by deployed military personnel may underlie symptoms and disease pathology. Much research has focused on the role of acetylcholinesterase inhibitors, such as pyridostigmine bromide (PB), and pesticides, including permethrin (PER) and the insect repellant N,N-diethyl-m-toluamide (DEET), as causative GWI toxins. Based on published reports and our own preliminary studies, we hypothesize that GWI-related chemical exposures result in the dysfunction of mitochondria, subcellular structures that regulate metabolism, programmed cell death, and immunity. Our laboratory focuses on mitochondria and their ability to activate the immune system, and we propose that exposure to GWI-related chemicals results in mitochondrial dysfunction, causing harmful immune responses that exacerbate GWI symptoms. To test this hypothesis, we will use a well-characterized model of GWI in which laboratory mice are exposed to GWI-related chemicals PB and PER to examine mitochondrial dysfunction and immune responses in the brain, muscle, and blood over a 1-year period. Through a collaboration with Ashok Shetty, a neurobiologist and experienced GWI researcher, we will correlate alterations in mitochondrial function and immunity with neuropathological, cognitive, and mood changes to determine mechanistic links between mitochondria, the immune system, and development of GWI-related symptoms. We will also explore whether a novel pharmacological approach to boost mitochondrial function and decrease inflammation will improve GWI-related pathology and neurobehavioral symptoms. To test this, mice exhibiting GWI-related symptoms will be fed chow containing bezafibrate, a Food and Drug Administration (FDA)-approved drug that increases the number of mitochondria and inhibits inflammatory processes, and monitored over time for improvement of symptoms. We expect the proposed research will significantly contribute to the GWI field and may have direct benefit to the quality of life and health of Veterans afflicted with GWI. Our study will advance the GWI field because it will: ? Further expand upon the idea that mitochondrial dysfunction underlies GWI. ? Support and expand upon the important concept of the immune system as a driver of GWI symptoms. ? Recognize for the first time that immune responses initiated by mitochondrial dysfunction are major drivers of GWI disease. Our study will improve the health of Veterans with GWI because it will: ? Show that a readily available drug can lessen GWI-related symptoms. Because bezafibrate is FDA-approved, beneficial outcomes observed in our model could very quickly lead to a clinical study on the effects of bezafibrate for improving the health of afflicted Veterans. ? Demonstrate that targeting mitochondria with drugs is an effective therapeutic strategy for treating GWI, potentially revealing additional therapeutic avenues by targeting mitochondria or mitochondria-related immune responses.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710446
Entities
People
- Andrew West
Organizations
- Texas A&M Health Science Center
- United States Army