BLRD RESEARCH CAREER SCIENTIST AWARD APPLICATION

The overarching goal of my research is to apply molecular neuroscience research to identify better treatments for Veterans conditions for which there are currently no effective treatments. Specifically, my work has focused on Alzheimer’s Disease (AD), Traumatic Brain Injury (TBI), Gulf War Illness (GWI) and Posttraumatic Stress Disorder (PTSD). Primarily, I use mouse models of these conditions, in order to explore the pathobiology of each condition over the mouse lifespan at the behavioral, biochemical and pathological level, and therein identify key targets for potential therapeutic intervention. Mouse models of AD, created using human AD-causing mutations (including those which I discovered), are commercially available; the mouse models of TBI, GWI and PTSD I have developed in-house. Using brain tissue and blood samples from these mice, we investigate cellular and molecular level changes that correlate with behavioral and pathological outcomes, in order to identify i) in the brain, potential molecular targets to intervene in the pathobiological sequelae; and ii) in the blood, potential diagnostic and theragnostic signatures. I work closely with many clinical collaborators to inform and direct the development and characterization of these models and to ensure that they have clinical relevance, in order to facilitate translation into clinical applications. This includes obtaining human blood and autopsied brain samples which can be used to verify and validate findings from our mouse models. Neuroinflammatory and neuroimmune mechanisms are emerging as key contributors in all of these conditions, but those umbrella terms encompass a multitude of detail into which we are now delving, including cell-specific and timing- specific responses. One of the unique aspects of my research programs has been our attention to lifelong consequences of the insults/exposures experienced in TBI, GWI or PTSD. These lengthy studies have resulted in e.g. 1) characterization of the lifelong (27 months old) consequences of single and repetitive mild TBI in mice aged 3 months at the time of injury – critically important data to understand the chronic effects of neurotrauma and provide a platform for studies of potential therapeutics; 2) characterization of the lifelong (25 months old) consequences of early life (3 months old) exposure to agents known to be contributory to GWI – very important for the current patient population who are suffering Today from GWI, more than 28 years after their toxic exposures; 3) demonstration of behavioral, biochemical and pathological outcomes in our novel PTSD mouse model 6 months after stress exposure –a translationally relevant preclinical platform in which to model our military and veteran populations with persisting PTSD. In these relevant laboratory models, we are identifying cell signaling pathways which, when modulated, mitigate against the negative outcomes of these various exposures. In GWI we have shown that the PPARa agonist, and dietary supplement, oleyoylethanolamide (OEA) is an effective treatment in our model, and have advanced into a Phase II human trial of OEA (ongoing). We have demonstrated that Nilvadipine (our lead anti-AD drug with anti-amyloid, anti-tau and anti-inflammatory properties) and Anatabine (a potent NFkB inhibitor / anti-inflammatory agent, previously available as a nutraceutical) each show positive outcomes in our mTBI models, including when administered at delayed timepoints post-injury (again highly relevant to the human mTBI patient population). My goal over the next ten years is to advance validated, well rationalized, novel treatments, derived from these research studies, into human clinical trials for AD, TBI, GWI and PTSD.