Improving Diagnostics and Treatments for GWI Females by Accounting for the Effects of PTSD
DoD GWIRP/ IIRA
Perform a secondary systems biology analysis for female subjects based on resources, methodology and results from our ongoing GWI research initiative to (1) isolate biobehavioral profiles that are specific to GWI alone and with PTSD, (2) evaluate how immune regulation in GWI is modified by probable PTSD diagnosis, and (3) use ongoing work in predictive modeling to assess possible changes to putative treatments of GWI.
Disentangling the Effects of PTSD from GWI for Improved Diagnostics and Treatments
DoD GWIRP/ IIRA
Perform a secondary systems biology analysis for male subjects based on resources, methodology and results from our ongoing GWI research initiative to (1) isolate biobehavioral profiles that are specific to GWI alone and with PTSD, (2) evaluate how immune regulation in GWI is modified in the presence of probable PTSD diagnosis, and (3) use ongoing work in predictive modeling to assess possible changes to putative treatments of GWI.
High Fidelity Design of Multi-modal Restorative Interventions in Gulf War Illness
DOD GWIRP/ IREA
Transition from idealized treatment regimens developed under previous award W81XWH-10-1-0774 (Broderick) by integrating drug pharmacokinetic properties into a model-based framework of HPA-immune interaction in order to identify optimally beneficial, low-risk and cost-effective re-purposing strategies that are immediately deployable as short exposure courses in GWI phase-I clinical trials. Specific aims include: (AIM 1) implementing relative dynamics of intracellular and cell-cell signaling, (AIM 2) incorporating available drug action data, and (AIM 3) Increasing the speed and thoroughness of current search capabilities for optimal intervention courses.
Testing the Model: A Phase I/II Randomized Double Blind Placebo Control Trial of Therapeutics: Liposomal Glutathione and Curcumin
DoD GWIRP/ IIREA
The goal is to implement a phase I/II placebo control double blinded 3 arm study of liposomal glutathione, curcumin and placebo in GWI in 75 veterans with GWI (25 per arm) and assess the safety, feasibility and clinical response to the interventions;. Integrate repeat assessment and modeling of dynamic response to exercise challenge in order to map homeostatic pathways before and after 12 weeks of intervention. Finally, assess antioxidant and methylation-related metabolic status prior to, during, and after acute exercise in GWI subjects before and after these antioxidant interventions.
Gender Differences in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
We aim to understand the mediators of persistence and relapse in men with ME/CFS, as we have in women. We will approach this by: (1) integration across several of the body’s regulatory systems of data and knowledge collected from disparate sources, and (2) mapping of the coordinated interactions between these physiologic systems and the potential for dysfunctional signaling networks. This project will extend this modeling of immune regulatory pathways and pathways that regulate latent viral expression in a way that will enable us to compare gender differences in illness mechanisms and explore gender-specific therapeutic targets.
Epigenetic Mediation of Endocrine and Immune Response in an Animal Model of Gulf War Illness
DoD GWIRP/ IIRA
The overall objective is to identify epigenetic mechanisms of altered Hypothalamic-Pituitary-Adrenal (HPA) axis and immune signaling in a mouse model of environmental exposures linked to GWI. DNA methylation and histone modifications will be examined in peripheral blood and the brain using a high-throughput genome-wide approach. This proposal builds on a funded GWIRP Consortium project examining gene regulatory dynamics in a mouse model of exposure to a sarin surrogate under stress/immune challenge.
Understanding Gulf War Illness: An Integrative Modeling Approach
Integrate two animal models of GWI with human clinical data to pinpoint the underlying mechanisms of disease and target treatment more effectively to re-establish normal well-coordinated signaling interactions. Specifically, our more detailed understanding of the dysfunction associated with key metabolic pathways involved in GWI would greatly expedite the identification of promising biomarkers for improved diagnosis over the short-term as well as selection and testing of more targeted therapeutic interventions over the longer term that will address the underlying mechanisms of disease.
A Translational Medicine Approach to Gulf War Illness: From Cells to Therapy
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 whole blood 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.
Women vs. Men with GWI: Differences in Computational Models and Therapeutic Target
We hypothesize that GWI affects regulatory function differently in women than in men, with implications on therapeutic management. The objective of this study is to improve our understanding of GWI pathogenesis in women by: (1) integrating data across several of the body’s regulatory systems, and (2) mapping of dysfunctional signaling networks in GWI in each sex.
Microbial Translocation in Chronic Fatigue Syndrome
NIH R21/ PA-08-247
To investigate the involvement of microbial translocation (MT) from the gut as a potential mechanism of disease progression and persistence in chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME).
Specifically, survey microbial translocation into peripheral blood of the biomarkers, lipopolysaccharide (LPS) and soluble CD14 (sCD14): at baseline, at 18 months as well as at two intervening time points corresponding to an episode of severe symptom onset. Then describe biomarker involvement in disease circuitry of immune, autonomic, neuroendocrine markers and clinical biomarkers using a systems biology framework.
Immunologic Mechanisms, Biomarkers and Subsets in CFS/ME
In this project extension, we will further investigate the potential illness mechanisms that drive the altered patterns of immune signaling that we observed and published, with the objective of designing a robust multiplex ELISA-based assay that captures the most clinically relevant interactions linking markers of immune, endocrine and nervous system function.
Study of Chronic Fatigue Syndrome using comprehensive molecular profiling with network and control theory
NIH R01/ PA08-246
To improve our understanding of CFS pathogenesis by: (1) integrating data and knowledge collected from disparate sources across several of the body’s regulatory systems, (2) mapping the interactions that emerge at multiple scales of biology and identifying potentially altered “wiring” in these signaling networks specific rapid response to exercise in CFS.
Post-exertion malaise in CFS: A systems biology approach to understanding brain, inflammation and behavior interactions
CFIDS Association of America
The main goal is to determine the dynamic relationships between brain structure and function, gene expression for sensory, adrenergic, and immune function and self-reported symptoms in chronic fatigue syndrome (CFS/ME) using an exercise model in a systems biology framework.
Theory-driven Models for Correcting “Fight or Flight” Imbalance in Gulf War Illness
DoD GWIRP/ IIRA
The goal of this project is to create a comprehensive engineering model of endocrine-immune interaction dynamics in order to (1) detect and identify theoretical failure modes of the HPA-immune axis that align with manifestations of GWI and CFS, and (2) use computer simulations to identify promising treatment strategies that exploit the regulatory dynamics of these systems in redirecting the overall system to normal coordinated activity.
The Use of Comprehensive Molecular Profiling with Network and Control Theory to Better Understand GWI and Model Therapeutic Strategies
DoD GWIRP/ IIRA
This is a data-driven study directed at identifying patterns of altered neuroendocrine-immune co-regulation in CFS and GWI subjects. This will be achieved by constructing empirical models describing the network kinetics of related biomarkers from time course data obtained during an exercise challenge.
Molecular Patterns of Persistent Immune Activation in a Post-infectious Adolescent Cohort
The CFIDS Association of America
The main goal is to describe deviations in endocrine-immune status and signaling that occur with onset and progression of post-infectious chronic fatigue syndrome (PI-CFS). We will focus on: (1) early detection and objective diagnosis by molecular and cellular profiling of peripheral blood; (2) effective treatment by applying network theory to identify characteristic deviations in endocrine-immune co-regulation.
Mechanistic analysis of microarray signatures in transplant rejection
University of Alberta N031000099
The main goal was to describe changes in genomic signatures resulting from surgical trauma alone and from trauma combined with allograft rejection. This project used extensive mouse experiments with isografts and allografts leading to the development of clinically relevant gene sets whose expression was indicative of the dominant mode of rejection. Expression of these gene sets eventually led to pre-surgical assessment of organ viability and expected post-transplant function.
Notification of award or JIT received, institutional agreements pending
The Use of B-Cell Depletion Therapy (BCDT) in Gulf War Illness: A Phase 1/2 Study
The objective of this Phase I/II study is to evaluate the safety and efficacy of rituximab versus placebo in patients with GWI, validate the initial presence of CNS autoantibodies and change with administration of rituximab as well as better understand the role of CNS autoantibody formation in the evolution of GWI and the ability to use this observation to define subgroups by biomarkers.