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Clinical Systems Biology Research

Current Research Projects

  • The Gulf War Illness Clinical Trials and Interventions Consortium (GWICTIC): The overall goal of the clinical trials outlined in this consortium is to target previously identified markers of disease activity, reset homeostasis with combination approaches with synergistic mechanisms of action or single agents with multiple disease targets, to improve outcomes and quality of life for those suffering with Gulf War Illness (GWI).
  • Immunomodulation in GWI: The objective of this study is to determine changes in the transcriptional regulation in each of the four major subtypes of immune cells (helper T cells, cytotoxic T cells, B cells and NK cells) caused by GWI and identify the role of cell-cell communication in pathobiology of GWI.

  • Using Periodic Spatial Disturbance to Manipulate Cooperation in Bacteria: Determine how periodic spatial disturbances caused by physical force affects cooperation in bacteria. Our long-term goalis to develop an understanding of how to manipulate bacterial cooperation to either enhance, or reduce, microbial growth, using methods that are less prone to evolved resistance.

  • Genomic approach to find female-specific mechanisms of GWI: The goal of this research is to identify novel, female-specific, genomic characteristics of the development of GWI for a better understanding of the causes of disease.

  • Disentangling the Effects of PTSD from GWI for Improved Diagnostics and Treatments: We propose to disentangle the effects of post-traumatic stress disorder from Gulf War Illness to understand the role that post-traumatic stress plays in the symptoms and perpetuation of Gulf War illness in men. Consistent with our group’s previous work, we will model and analyze the changes in the immune and stress responses in subjects across time following a graded exercise challenge using a dynamic modeling approach.

  • Improving Diagnostics and Treatments for GWI Females by Accounting for the Effects of PTSD: We propose to disentangle the effects of post-traumatic stress disorder from Gulf War Illness to understand the role that post-traumatic stress plays in the symptoms and perpetuation of Gulf War illness in women. Consistent with our group’s previous work, we will model and analyze the changes in the immune and stress responses in women across time following an exercise challenge using a dynamic modeling approach.

  • High Fidelity Design of Multi-modal Restorative Interventions in Gulf War Illness: 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. My role is to give clinical context to the models that are developed.

  • 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.

     

Past Research Projects

  • Testing the Model: A Phase I/II Randomized Double-Blind Placebo Control Trial of Therapeutics: Liposomal Glutathione and Curcumin: 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: (i) integration across several of the body’s regulatory systems of data and knowledge collected from disparate sources, and (ii) 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.
  • Theory-driven Models for Correcting “Fight or Flight” Imbalance in Gulf War Illness: The goal of this project is to create a comprehensive engineering model of endocrine-immune interaction dynamics in order to (i) detect and identify theoretical failure modes of the HPA-immune axis that align with manifestations of GWI and CFS, and (ii) 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.

  • Post-exertion malaise in CFS: A systems biology approach to understanding brain, inflammation and behavior interactions: 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.     

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