Traumatic brain injury (TBI) and post-TBI neurological sequelae are a major medical concern for US military veterans. There is no effective therapy to battle the catastrophic neurological disabilities after TBI, in part because most neuroprotective therapies against TBI target gray matter but neglect the importance of white matter (WM) injury, the degree of which dictates the severity of long-term neurological deficits. A persistent proinflammatory microenvironment after TBI is considered one underlying mechanism that exacerbates WM injury and hinders WM repair. Microglia and macrophages (Mi/MΦ) are important mediators of post-TBI immune and inflammatory responses and can assume diverse functional states in response to specific microenvironmental signals. Accumulating evidence suggests that the different functional phenotypes of Mi/MΦ contribute considerably to the regulation of inflammatory status of injured WM and ultimately impact WM integrity. Specifically, an inflammation-resolving and protective/reparative phenotype of Mi/MΦ is essential for mitigating WM injury and facilitating WM repair because they resolve local inflammation, clear broken myelin sheath or cellular debris, and supply trophic factors for brain remodeling. The key molecular switches and networks that determine the overall functional state of Mi/MΦ after TBI are poorly understood. To fill this critical scientific gap, we propose to investigate salt-inducible kinases (SIKs) as novel regulators of Mi/MΦ functions after experimental TBI. SIKs potently control gene expression by directly acting on several specific transcriptional regulators. Thus, SIK activation lies at the apex of a decision tree for arbitrating between polymorphic, often-opposing immune responses in Mi/MΦ. The scientific premise underlying the engagement of SIK as a candidate biological target for TBI is its ability to titrate immune balance toward inflammation-resolving and protective/reparative phenotypes, while avoiding indiscriminate suppression of immune function. The scientific premise of this proposal is also strengthened by our new preliminary discoveries: 1) TBI elevates SIK1 expression and activity (phosphorylation) in Mi/MΦ but not in other brain cells in mice; 2) Tamoxifen-induced selective knockout of SIK1 in Mi/MΦ (mKO) improves long-term sensorimotor functions and spatial memory after TBI, confirming a crucial role of Mi/MΦ SIK1 in TBI neurological outcomes; 3) Mechanistically, SIK1 mKO drives Mi/MΦ toward an inflammation-resolving and protective/reparative phenotype after TBI, thus restricting axonal injury and promoting WM repair; 4) Intraperitoneal delivery of YKL-05-099 (YKL), a novel selective SIK inhibitor, attenuates neuroinflammation and neurological deficits after TBI. Accordingly, the proposed studies will test the core hypothesis that genetic deletion or pharmacological inhibition of SIK1 improves white matter restoration and long-term TBI outcomes by dual mechanisms: 1) protecting ...