Breaching CNS barriers: Deciphering the spatiotemporal regulation of immune cell surveillance following blast TBI

White River Junction Va Medical Center, White River Junction VT

Investigators

Abstract

Background: Dr. Krista DiSano currently serves as a Research Health Scientist at the White River Junction VA Healthcare System (WRJ-VAHS). She is an active member of the VA and Dartmouth scientific community, including the WRJ Translational Neuroscience Research Group directed by her primary mentor, Dr. Paul Holtzheimer. Since joining this group, her research has focused on elucidating the mechanisms regulating inflammation following shockwave-induced blast traumatic brain injury (bTBI). Military personnel are particularly vulnerable to bTBI, which is considered a signature injury of recent wars. Common complications following blast exposure include chronic neuropsychiatric impairments, including cognitive deficits and mood disorders, which significantly affect quality of life. The underlying biological processes responsible for these outcomes have not been fully characterized, but putative mechanisms include neuroinflammation. It has been suggested that chronic neuroinflammation may contribute to neuropsychiatric impairments following blast exposure, including anxiety and depression. Ongoing work by our laboratory and others is centered on evaluating the utility of immunomodulation to improve outcomes. We posit that defining mechanisms regulating immune cell infiltration into the CNS following bTBI will expand the implementation of immunomodulation interventions for blast injury and guide personalized treatment. The current study aims to begin to address these gaps in our knowledge by defining: 1) How immune cells enter the CNS following bTBI; 2) Whether immune cell spatial location in the CNS influences post-injury outcomes; and 3) The origin of immune cells recruited to the CNS following bTBI. Dr. DiSano’s long-term goals are to identify factors supporting non-resolving neuroinflammation, elucidate immune cell function after injury, and screen immunomodulatory therapeutics that may improve outcomes. Her ongoing studies employ a pre-clinical, rodent model of bTBI to explore the complex inflammatory processes following bTBI that cannot be addressed in clinical settings. The proposed project is an extension of her VISN1 CDA-1 that focused on 1) evaluating how different cells of the immune system respond to brain injury, and 2) identifying structural changes that promote cell entry into the CNS (e.g., blood- brain barrier disturbances). As part of this work, she demonstrated that reducing immune cell entry into the CNS via immunomodulation reduced chronic neuroinflammation, including microglial activation. These and other preliminary findings guided the current project goals. Current Proposal: Dr. DiSano’s mentored training and research will utilize several novel methodologies to investigate how immune cell trafficking, spatial location, and origin impacts the CNS microenvironment and behavioral consequences. The overall hypothesis postulates that following blast injury, the CNS responds by creating a niche for immune cell entry into diverse subcompartments (e.g., parenchyma, meninges, perivascular spaces) and immune cell persistence in these spaces influences tissue injury/repair and behavioral outcomes. Dr. DiSano will leverage several immunomodulatory agents to investigate this hypothesis. It is anticipated that this work will provide valuable insight to guide precision immunotherapy to improve recovery following bTBI. Relevance: The high prevalence of bTBI in service members warrants effective interventions. Moreover, the debilitating cognitive and psychiatric complications often associated with bTBI requires the development of novel treatment that targets underlying mechanisms, including neuroinflammation. The proposed training and research activities will investigate neuroinflammatory processes after blast exposure and will ultimately support Dr. DiSano’s long-term career goal to develop and implement efficacious immunomodulatory treatments to meet this urgent need.