PROJECT SUMMARY Traumatic brain injury (TBI) is a leading cause of cognitive and motor impairment in the United States and is estimated to result in long-term disability in approximately 1 to 2 percent of the population. Currently, all pharmacological therapies focused on limiting neurodegeneration after TBI have been unsuccessful in preventing secondary sequelae. Therefore, the prevention of secondary cognitive and motor sequelae is a significant unmet need in neuroscience research. Long myelinated axons within white matter are vulnerable to physical trauma and disruption of these tracts after TBI results in white matter atrophy that is strongly correlated with both cognitive and motor dysfunction. Myelin is generated by mature oligodendrocytes and is essential for robust propagation of action potentials and for the survival and integrity of neuronal axons. Oligodendrocyte death and demyelination can therefore result in increased vulnerability of axons, predisposing them to degeneration. Although progressive and chronic white matter abnormalities are reported after TBI, the mechanisms initiated by mechanical strain on brain tissue that contribute to oligodendrocyte dysfunction and white matter loss remain poorly defined. My preliminary data show that multifactorial TBI induces dynamic changes in the oligodendrocyte lineage. With publicly available RNA sequencing data I demonstrate that Yes-associated protein (YAP) may transcriptionally activate genes upregulated in oligodendrocyte progenitor cells (OPCs) after TBI. YAP and its co-transcriptional activator PDZ- binding motif (TAZ) are the nuclear effectors of the Hippo signaling pathway, a highly conserved pathway that regulates organ growth and regeneration. Oligodendrocytes and OPCs are known to respond to mechanical stimuli such as shear stress through the actions of YAP, however the consequences of YAP hyperactivity in this lineage are unknown. I demonstrate that YAP hyperactivity is sufficient to impair OPC differentiation. The aims of this proposal will seek to define 1) how modulation of YAP activity affects differentiation and proliferation of OPCs and 2) whether YAP maintains the progenitor state in OPCs and unlocks a cryptic transcriptional program when hyperactivated. These aims will be achieved using a combination stem cell biology and genomics techniques, in conjunction with in vivo disease modeling. Understanding the functional consequences of YAP activity in the oligodendrocyte lineage will offer new opportunities to prevent or reverse the neurological sequalae of traumatic brain injury that affect millions of Americans.