A Translational Medicine Approach to Gulf War Illness: From Cells to Therapy

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Current treatments used for Gulf War illness (GWI) are directed at the symptoms associated with the disease and do not target the underlying disease process. Investigators from the Miami VA and Nova Southeastern University developed a data set consisting of potential mediators of GWI persistence and relapse after an exercise challenge using gene expression as well as measures of immune, autonomic, and neuroendocrine function. This rich and complex data set was examined with a systems biology analytic approach, which revealed a markedly abnormal balance within and between major regulatory systems. Our work has identified 5 targets for in vitro validation: (a) modulation of inflammatory cytokines, (b) changes in IL-23/Th17/IL-17 axis, (c) the recovery of NK cell function, and (d) the suppression of excessive NF-kB activity. The objectives of the proposed study are to determine if intervening at these therapeutic targets selected via computational modeling will act as predicted and normalize immune and neuroendocrine function in an in vitro system. The study will have 2 phases: an exploration/ screening phase and a validation phase. The screening phase will be conducted on 17 repurposed drugs. These will be assessed in vitro using peripheral blood mononuclear cell (PBMC) cultures from 40 GWI patients and 40 matched controls. The most promising 5 drugs will be validated in PBMCs from a new cohort of 40 GWI patients and 40 matched controls. A desirable treatment will produce a significant treatment effect (p<0.05) in the majority of cell populations, cytokine expression, and NK cell functional markers that are abnormally expressed in GWI. A desirable treatment will also produce a co-expression pattern of cell subsets, cytokines, and NK cell functional markers in the cells from GWI subjects that is statistically indistinguishable (p = 0.05) from that of the matched healthy control counterpart. In the event of two or more drugs producing similarly positive results, we will pick the repurposed over the pipeline agent, a well-established safety record taking priority. Similarly choosing between two repurposed drugs, the drug with the lowest risk in terms of side effects will be used. A second consideration would be cost.