ABSTRACT Neuroinflammation has emerged as a critical component of secondary injury following brain trauma. Recent pre- clinical studies have shed light on the neurotoxic effects of peripheral-derived monocyte/macrophages (PDM). Our preliminary findings suggest this response may be dampened in the presence of juvenile-derived murine PDMs, however the cause of this neuroprotective response remains unknown. The research objective of this application is to characterize the cellular and molecular mechanism(s) underlying the divergent, age-dependent PDM response and their role in mediating neurovascular dysfunction following TBI. Our proposal builds upon extensive preliminary and published data demonstrating a distinct age-at-injury response following TBI. Juvenile- derived PDMs display reduced pro-inflammatory phenotype, and adult PDM depletion and replacement with those from juvenile mice confer neuroprotection. Moreover, we discovered that PDM-specific Tie2/EphA4 receptor crosstalk regulates their pro-inflammatory state across the age spectrum. We hypothesize that age- related differences in the PDM response underlie divergent outcomes following TBI. We will employ cell-specific depletions, and PDM replacement as well as novel transgenic murine models. These approaches will include rigorous behavioral, histological and innovative low-input genome-wide omics assessment of the relevance and mechanism(s) of PDM age on injury outcomes. We will also provide a framework for retooling the neuroinflammatory response to accelerate pro-recovery and dampen pro-inflammatory processes after TBI.

PROJECT NARRATIVE Limited information exists pertaining to the physiological relevance of innate immune regulation across the age spectrum following TBI. Completion of these studies will advance our understanding of the key regulators involved in monocyte/macrophage responses and neurovascular health in TBI pathophysiology. Exploiting the pro-resolving phenotype of juvenile- derived PDMs may provide a novel restorative intervention aimed at improving TBI outcomes and reveal novel targets for drug discovery.