Our research team has been studying Gulf War Veterans with chronic gastrointestinal pain disorders for over a decade (Dunphy et al., 2003). Many Gulf War Veterans developed chronic gastrointestinal pain during their deployment to the Persian Gulf in 1990-91. The pathophysiologic mechanisms of this chronic gastrointestinal pain are not well understood but cause significant morbidity in our Gulf War Veteran population. The mechanisms underlying this chronic gastrointestinal pain disorder in Gulf War Veterans need to be established. In preliminary studies, we have identified unique microRNAs (miRNAs) present in the colon tissue of Gulf War Veterans who returned with chronic gastrointestinal pain. Based on these preliminary findings, our overall hypothesis is: Aberrant expression of specific miRNAs dysregulates downstream miRNA targets (?glutamate & ?opioid receptors) that cause, contribute to, or facilitate chronic gastrointestinal pain in Gulf War Veterans. We have established techniques to determine inter- and intra-cellular roles of miRNAs in the epigenetic regulation of the expression of their down-stream target genes. These methods include: (i) interaction analysis of miRNAs; (ii) transfection of miRNAs into cultures of human colonic epithelial cells; into rat colonic epithelial cells and into rat dorsal root ganglion cells (Aim 3) (iii) in vivo injection of miRNAs in a validated rat model to test for a reduction in visceral hypersensitivity (Greenwood-Van Meerveld et al., 2015; Zhou et al., 2015). Identifying the role of miRNA signaling should: (i) Fill an important gap in our understanding of chronic gastrointestinal pain, especially the dysregulation of nociceptive pathways. (ii) Lead to therapeutic strategies that use small molecules that mimic or inhibit specific miRNAs that target gene expression. This will overcome a critical barrier - lack of effective treatments for our Gulf War Veterans who suffer from chronic gastrointestinal pain disorders and lead to the development of novel, miRNA-based sets of diagnostic markers.
Significance and Relevance to Gulf War Veterans: Chronic gastrointestinal pain is common among Gulf War Veterans who returned from active combat deployment. A major goal of the proposed studies is to determine the mechanisms that lead to chronic gastrointestinal pain in deployed Gulf War Veterans. The proposed studies will provide: (1) an innovative model to explain chronic gastrointestinal pain in Gulf War Veterans that were deployed into war zones; and (2) a novel way to treat them. Indeed, our model, which holds that the above gastrointestinal pain is due to altered miRNA signaling is supported by our preliminary data. Given that there are currently no specific treatments for these disorders, and that current symptomatic approaches are far from ideal, proof of principle of our model would be an extremely important advance as it would not only have a beneficial impact on the health of many thousands of our Veterans, but also it would substantially reduce the many negative economic effects of this ailment on the VA health care system.
| Zhou, QiQi; Verne, Meghan L; Zhang, Buyi et al. (2018) Evidence for Somatic Hypersensitivity in Veterans With Gulf War Illness and Gastrointestinal Symptoms. Clin J Pain 34:944-949 |
