An Integrated Genomics and Cell Biology Approach to Correlate Novel GWI Indicators of Infections and Neuroinflammatory Mechanisms with Targeted Drug Therapy
Abstract
Gulf War Illness (GWI) is a complex condition that is associated with a variety of symptoms including fatigue, headache, memory problems, muscle and joint pain, gastrointestinal issues, neurological problems, hormonal imbalance and immune dysfunction. The condition appears to affect both men and women who were deployed to the GW, with up to one-third of these affected Veterans remaining ill today. Currently, little is known about what causes the onset and progression of the disease. Diagnosis is made based on a process of elimination, and treatment involves symptom management rather than targeting the underlying mechanism of the disease. While little is known about the inner workings of GWI, recent data have suggested that the condition is likely caused by a combination of factors including an individual s genomic make-up and environmental exposures, such as toxic chemicals and/or pathogens. Further exacerbation or chronic stress exposure during and after wartime may also contribute to aggravation and persistence of GWI. The goal of our research efforts is to develop a better understanding of the genomic characteristics as well as of the alterations in cellular mechanisms that contribute to the development of the disease. Identification of disease targets will lead to designed therapeutic intervention. Specifically, our more detailed understanding of the dysfunction involved in GWI would greatly speed up the identification of promising biomarkers to help improve diagnosis and treatment. There are two components to our research efforts: (1) genomic evaluation and (2) uncovering cellular mechanisms. In an effort to understand what is occurring on a genomic level, we aim to understand the changes that occur in RNA as well as in DNA activation/deactivation in individuals with GWI as compared to their healthy counterparts exposed to similar wartime stressors. This will provide us with a better understanding of how changes in an individual s genomic make-up cause them to develop the illness versus those who remain healthy today. While it is important to gain an understanding into what specific genes change their expression in the onset and progression of GWI, it is equally important to understand why these genes change their expression. Therefore, on a cellular level, we want to understand how the presence of prior and current illnesses can lead to the onset and progression of GWI as well as potentially alter specific mechanisms that are vital for cell survival, function, and immune defense. We will test one known Food and Drug Administration (FDA)-approved drug (statin) for impacts on GWI intracellular mechanisms for possible reassignment. We will directly evaluate GWI-specific genomic differences and correlate these differences with alterations on fundamental cellular mechanisms. Our studies will contribute to the elucidation of differential mechanistic pathways that occur in GWI and their correlation to genomic changes, cellular activity, immunity, and antiviral activity. One of the most compelling aspects of this proposed research study is our ability to work closely and share our data with the previously Department of Defense-funded GWI consortium (GW120045, Dr. M. Morris, Principal Investigator [PI], Drs. N. Klimas and G. Broderick, Co-PIs). We also do not need to recruit new patients, as we will be able to access samples already collected from the consortium. The consortium developed a translational model of GWI, integrating both clinical and basic research using systems biology approach. This computational biology approach will aid our research team to identify signaling mechanisms relevant to GWI and outline the most promising biomarkers tied to these signaling pathways for selection and testing of therapeutic interventions. These tests not only improve symptomatology but also aid on resetting normal well-coordinated signaling interactions. The consortium is designed for rapid identification of mol
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510163
Entities
People
- Paula Waziry
Organizations
- Nova Southeastern University
- United States Army