Pericyte Mechanisms in Traumatic Brain injury Pericyte mechanisms are poorly understood in TBI. This is the major gap in knowledge that we seek to address. Our pilot data (some published in Choi et al, Nature Medicine 2016) suggest that (a) pericytes are widely damaged in mouse models of concussion or controlled cortical impact, (b) pericyte injury involves HIF- 1a signaling, (c) disruption of pericyte-neural stem cell (NSC) crosstalk perturbs neurogenesis and interferes with TBI recovery, (d) pericyte-NSC crosstalk may involve nitric oxide (NO) pathways, (e) pericytes may also communicate with oligodendrocyte precursor cells (OPCs), and (f) treatments with carbon monoxide (CO) that enhance heme oxygenase (HO-1) signaling may restore pericyte crosstalk and improve recovery after TBI. Based on these pilot data, we propose this overall hypothesis: TBI triggers HIF-1a-mediated injury to pericytes and disrupts pericyte-NSC-OPC crosstalk thus interfering with endogenous recovery. If true, this hypothesis may have translational significance, i.e. rescuing “help-me” signaling between pericytes, NSCs and OPCs may improve gray and white matter recovery after TBI. We will test this hypothesis in four integrated aims. In Aim 1, we investigate cellular mechanisms that allow pericytes to support NSCs and OPCs, and ask how HIF-1a-mediated pericyte injury disrupts these crosstalk mechanisms. In Aim 2, we test CO as a way to augment HO-1 signaling for protecting pericytes. In Aim 3, we dissect integrin and HIF mechanisms for pericytes, NSCs and OPCs in vivo using two TBI models (mild-to-moderate concussion and more severe controlled cortical impact). In Aim 4, will use the two mouse models of concussion and controlled cortical impact to test the utility of CO-HO-1 signaling as a therapeutic approach for restoring pericyte-NSC-OPC crosstalk and improving recovery after TBI. To assess causality in our pathways, we will conduct gain and loss- of-function experiments using cell culture, in vivo mouse models, pharmacologic inhibitors, dominant mutant constructs, siRNA and knockouts, optical imaging and long-term neurological outcomes. This project should define a novel mechanism wherein widespread injury to pericytes underlie not only acute vascular injury after TBI, but also disrupts pericyte-NSC-OPC crosstalk pathways. Our findings may provide a new conceptual framework for potentially targeting pericyte mechanisms after TBI.

Project Narrative for R01 resubmission by Lo Pericyte Mechanisms in Traumatic Brain Injury We know that pericytes are important in cerebrovascular disease. We know that vascular responses are important in TBI. Hence, it is likely that pericyte mechanisms are important for TBI. But these pericyte mechanisms in TBI remain mostly unknown. This is the major gap in knowledge we seek to fill. Our studies should define novel molecular pathways that allow pericytes to communicate with neural stem cells and oligodendrocyte precursor cells thus promoting neurogenesis and oligodendrogenesis. Our findings may eventually be useful for developing new therapies to improve recovery after TBI.