Project Title

Understanding Gulf War Illness: An Integrative Modeling Approach

Principal Investigator/Project Director

Mariana Morris

Colleges / Centers

Dr. Kiran C. Patel College of Osteopathic Medicine

Funder

DOD - U.S. Army Medical Research Acquisition Activity

Start Date

9-30-2013

Abstract

Background: This consortium consists of thought leading experts with a focus that is complementary, related to, or focused on GWI. This team combines researchers with expertise in basic and clinical research along with those with expertise in drug development and testing. Under the leadership of Dr. Mariana Morris, Dr. Nancy Klimas and Dr. Gordon Broderick, the team is expert in neurotoxicology, animal modeling, computational modeling, clinical research, drug development and drug repurposing. There are four main cores that contribute to the overall goal of the consortium including a basic science core, clinical science core, computational core and therapeutic science core. Together, this integrated consortium will provide the best opportunity for advancing GWI diagnosis and treatment. Objectives: The goal of the consortium is to develop a translational model of GWI, integrating both clinical and basic research using a systems biology approach. This approach will enable our consortium to identify signaling mechanisms relevant to GWI and outline the most promising biomarkers tied to these signaling pathways for selection and testing of therapeutic interventions to not only improve symptomatology but also reset homeostasis. Upon completion of the studies involved in this consortium, we will have identified pathways and biomarkers tied to regulatory dysfunction in GWI, established targets for therapy, and performed translational studies. Research Plan: The studies in this consortium will be designed for rapid identification of molecular targets and prediction of effective therapeutic interventions. Specifically, we will have a stronger understanding of the metabolic signaling mechanisms involved in the disruption of normal well coordinated interactions involved in autonomic cardiovascular function, immune response, and endocrine function. We will also have initial translational animal and human data to support clinical trial designs and have completed initial phase I investigations. The research plan includes the following research study objectives: • Study 1: To characterize the autonomic neural/adrenal dysfunction in a mouse model of GWI using validation and direction from a computation biology approach based on systems biology and existing human networking data. • Study 2: Further characterize the molecular and cellular phenotype of GWI in a mouse model to understand the contribution of glial cell subtypes and examine the potential role of the stress response in persistence of the illness. • Study 3: Integrating human and animal research by applying a computational systems biology approach to identify mediators of the deregulated balance of complex homeostatic networks in GWI and testing putative therapeutics in the computational model. • Study 4: To evaluate therapeutics suggested by the computational model in the GWI animal models, refine the models and survey libraries of drugs in the dynamic modeling animal platform, delivering the two or three most favorable for human testing. • Study 5: To perform translational human clinical trials using our dynamic challenge to evaluate homeostasis “reset” as well as preliminary safety and efficacy after exposure to interventions identified in studies 3 and 4. Impact: Conventional GWI treatments have failed to effectively treat the underlying dysfunction associated with GWI, aside from managing symptomatology. This consortium will pinpoint underlying mechanisms of disease and target treatment more effectively to re-establish homeostatic function to return the body to 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 diagnosis as well as selection and testing of more targeted therapeutic interventions over the longer term that will address the underlying mechanisms of disease

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