CMA: IMMUNE/INFLAMMATORY PRIMING IN EXACERBATING RESPONSES TO GWVI STRESSORS: IMPLICATIONS FOR GWVI TREATMENTS

Project Details

Description

Project Summary/AbstractThis Collaborative Merit Review Award for Research (I01) proposed in response to RFA BX-18-007 from theVeteran Health Administration is a joint effort by investigators from the JJ Peters VA Medical Center (Bronx,NY) Project 1, Arnold School of Public Health and Wm Jennings Bryan Dorn VA Medical Center (Columbia,SC) Project 2, Brain Science Center VA Medical Center (Minneapolis, MN) Project 3. We define a vision foran integrated and multidisciplinary program of preclinical research projects all linked by the ultimate goal tobetter characterize the mechanism of persistent and aberrant immunological activity in Gulf War VeteranIllnesses (GWVI) by developing experimental model systems, with the ultimate goal of developing noveltherapeutic interventions. Gulf War Veterans’ Illnesses is a multifaceted disorder characterized by a range ofsymptoms including cognitive impairment, fatigue, pain, mood disorders, among others. Recent evidencesuggests that the onset and progression of these symptoms may be the result of disequilibrium in thesesubjects’ immune systems. During deployment GWV were exposed to a unique variety of toxic agents thatwere specific to the Gulf War theatre, such as pyridostigmine bromine (PB), diisopropyl fluorophosphates(DFP), permethrin, and depleted uranium which current evidence indicates lowered thresholds toimmunological responses and resulted in the persistent and heightened activity of certain arms of the immunesystem; a phenomenon best described as “immunological priming”. In addition, they received more than 20vaccines that could have overloaded the immune system. In support of these considerations, subjects withGWVI often have shown pathological signatures in common with autoimmune disorders and generalizedinflammatory disorders, such as increased plasma concentrations of pro-inflammatory cytokines, unspecifictissue degeneration, and organ failure. Based on this concept, the three proposed collaborative researchprojects were designed to better understand how primed immune systems may contribute to GWVI- typephenotypes by exploring how multiple GWI conditions recapitulated in animal models may synergize andeventually provide new mechanistic evidence for translation studies. For example, Project 2 was designed tounderstand how GW toxin induced gut inflammasome activation causes gut dysbiosis and may lead topersistent or heightened immune-inflammatory responses and GWVI symptoms. As the goal of Project 3 isdesigned the hypothesis that lack of specific immunity leads to vaccine-induced inflammatory reaction in thebrain, Project 2 will collaborate with project 3 to test the contribution of inflammasome priming and geneticdiversity to gut dysbiosis and persistent immunological responses. Similarly, Project 1, which is designed totest how immunological priming may heighten inflammatory responses to psychological stressors, willcollaborate with project 2 and project 3 by exploring how the NLRP3 inflammasome may contribute toheightened inflammation induced by gut dysbiosis or HLA polymorphisms, respectively. The outcome ofthese studies is of great interest not only because this will establish a novel link between inflammasomepriming, genetic diversity and gut-dysbiosis toxemic response, but it will also provide insight to test noveltherapeutic approaches that target the persistent activation of the immune system, either usingimmunotherapeutic approaches against vaccine toxins, probiotics to attenuate gut dysbiosis. Our proposedstudies are innovative in terms of their scope, since it will fill the fundamental gaps needed for futuretranslational studies. Most importantly our multiscale technological innovative approaches, which includeknockout murine models of GWVI, including for the HLA and NLRP3 proteins, will enable our interdisciplinaryresearch team with outstanding expertise in neuroscience, pharmacology, microbiology, chemistry tothoroughly investigate the molecular mechanisms underlying the etiology of GWVI.

StatusActive
Effective start/end date1/07/1930/06/23

Funding

  • U.S. Department of Veterans Affairs

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