Probing Neuroinflammation in GWI via Studies on Gulf War Veteran-Derived Microglia
Abstract
Overarching Challenges: The proposed studies are relevant to two overarching challenges listed for the GWIR Program: (1) Treatments – Eliminate the health consequences associated with Gulf War Illness (GWI) and/or revolutionize treatment. 2) Consequences – Determine whether GWI alters risk for developing neurological conditions or other severe conditions; or whether GWI alters outcomes of other infections/ diseases. Rationale: GWI affects nearly 40% of military personnel served in the 1990-1991 Gulf War (GW). The altered function of the brain is one of the most bothering health issues in Veterans with GWI. The symptoms include difficulties for memory formation and memory recall, concentration issues, mood swings, and chronic pain. Epidemiological studies suggested that exposure to one or more GW-related chemicals or interaction of these chemicals with war-related stress is the cause of GWI in a substantial proportion of Veterans. In the 30 plus years after the GW, progress has been made in diagnosing symptoms linked to changes in the function of multiple organ systems, including the brain. Also, the pathology underlying the persistent brain-related problems has been identified in animal models. Such studies have shown that combined exposure to low doses of GWI-related chemicals is detrimental to the central nervous system function. Furthermore, neuroinflammation, particularly over activation of microglia, has been identified as one the most conspicuous changes observed at chronic time points in animal models of GWI. Microglia are the resident immune cells in the brain – in normal conditions, microglia serve as housekeeping cells and maintain equilibrium in the brain. Microglia gobble up the dead cells and the excess proteins and waste products in the brain, destroy and eat the invading microorganisms, and sculpt connections between neurons to make them function better. In chronic brain diseases, they become supersensitive and continuously release a type of proteins called proinflammatory cytokines. Such cytokines cause sickness behavior and brain fog with symptoms such as impaired thinking ability, concentration, decision-making, memory formation, retention, or recall. Advanced imaging studies on Veterans with GWI have also suggested the presence of such altered microglia in Veterans with GWI. However, it remains to be validated whether the extent of microglia-related changes observed in animal models of GWI also manifest in Veterans afflicted with chronic GWI. With the advancements in the stem cell field, it is now feasible to study specific cell types in human patients. For example, a sample of skin cells or blood cells from patients can be converted into induced pluripotent stem cells, capable of producing any cell type in the body and then into the desired cell type. Using such technology, one can now create and study microglia from human induced pluripotent stem cells generated from patients afflicted with various conditions. For example, studies have shown that, unlike normal microglia from healthy individuals, microglia from Alzheimer s disease (AD) patients are abnormal. Their ability to mop up the dead cells, cellular debris, or abnormal proteins was reduced. Such abnormal microglia also presented hyperactivity to inflammatory stimulants – they secreted vast amounts of proinflammatory cytokines capable of causing memory problems. In this proposal, we propose creating and studying microglia from induced pluripotent stem cells generated from GW Veterans with or without GWI. The required induced pluripotent stem cell lines are already available in the laboratory of Co-Investigators, Dr. Peter Baas (Drexel University) and Dr. Kimberly Sullivan (Boston University) as part of Boston GWI Consortium and Boston Biorepository and Integrative Network (BBRAIN) for GWI. The proposed studies would likely help in understanding changed microglial function and chronic neuroinflammation in GWI. Also, the finding
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210565
Entities
People
- Ashok Shetty
Organizations
- Texas A&M Health Science Center
- United States Army