Investigation of Mitochondrial Epigenetic Changes as a Biomarker for Gulf War Illness and an Outcome Measure in Response to Therapy
Abstract
Approximately 697,000 men and women served in operations "Desert Shield" and "Desert Storm" from August 1990 to June 1991, and between 25%-33% continue to suffer from Gulf War Illness (GWI) a chronic, multisymptom illness. Veterans with GWI exhibit persistent health issues such as fatigue, gastrointestinal problems, idiopathic pain, musculoskeletal problems, and neurological symptoms, with memory problems being one of the most commonly reported symptoms. Veterans continue to report symptoms that cannot be easily diagnosed but are, in many cases, debilitating. In addition, there are no reliable diagnostic tools available, treatment strategies are in their infancy, and the cause is poorly understood. Thus, there remains an urgent need to develop effective and reliable evidence-based biomarkers that can be used for diagnostics and as an output measure for treatment strategies, which is tailored to distinguish GWI-affected Veterans from healthy controls. Our solution to the setback of a lack of peripheral biomarkers for GWI diagnosis and clinical management is to apply the knowledge we gained in preclinical animal models to generate biomarker profiles. We will be using the already banked tissue from Gulf War (GW) agent-exposed mice (generated from a previous funding source, GW100076 to Dr. Ait-Ghezala), which display key features of the disease relevant to Veterans with GWI such as central nervous system (CNS) and peripheral disturbances. Markers of genetic modifications (epigenetics) are very important in the clinical practice, serving as a key function in categorization of staging, classification, as well as guiding clinical management of diseases. However, to date, insufficient attention has been paid to the impact of mitochondrial epigenetics in the study of human diseases with respect to drug, chemical, and environmental exposure, which can alter epigenetic marks. Furthermore, epigenetic modifications are induced by internal and external cellular stimuli including but not limited to exposure to pollutants (such as those to which our Veterans have been exposed to during the GW era), oxidative stress (such as the one caused by GW agents exposure), temperature, nutrients, and aging. Therefore, more focus is required upon mitochondrial epigenetics in order to understand mitochondrial dysfunction in response to the environmental exposures that are implicated in GWI. To accomplish the goal of identifying biological and genetic variability potentially linked to differences in vulnerability to GW exposures and discovering markers indicative of past exposure to GW-related neurotoxicity, we will investigate the epigenetic changes in mitochondrial DNA and nuclear encoded mitochondrial genes in a cell model exposed to GW agents. Then, we will evaluate the epigenetic changes in our mouse model that recapitulate GW symptoms as well as in the model developed by our colleague, Dr. O’Callaghan. Finally, in the third aim, we will investigate the significant epigenetic markers identified in Aims 1 and 2 in plasma samples from a cohort of GW Veterans from banked blood specimens form the Roskamp Institute clinic and the Gulf War Illness Research Consortia and compare them to controls, thereby developing an epigenetic panel of candidate biomarkers. The Roskamp Institute is committed to identifying diagnostic tools and effective treatments for GWI. If, as we hope, the biomarker panel we identify shows to be reliable in our mouse model, then the roadmap for future directions is clear. Our prior experience translating preclinical findings into human clinical trials, in GWI and other CNS conditions, ensures that our preclinical work is always critically evaluated for translational potential. This will be greatly facilitated by the Roskamp GWI clinic, the Gulf War Illness Research Program-supported clinical trial consortium and our team, which are highly skilled and experienced in discovery of biomarkers. We are therefore conf
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010818
Entities
People
- Ghania Ait-Ghezala
Organizations
- Roskamp Institute
- United States Army