Cell Specific IL-1R1 in Focal and Diffuse TBI Models

Traumatic brain injury (TBI) is a strong environmental risk factor for dementia. The heterogeneity of TBI phenotypes (e.g., focal contusion vs. diffuse injury) is thought to contribute to the failure of clinical trials. Though pathoanatomically distinct, controlled cortical impact (CCI) and diffuse closed head injury (CHI) models each activate interleukin-1b, but cognitive outcome in IL-1 receptor 1 knockout (IL-1R1 KO) mice is improved after CHI but worse after CCI1, suggesting that targeting IL-1b may be harmful in some TBI patients. While provocative, these studies are inconclusive because of the potential for off target and developmental effects in constitutive IL1R1 KO mice. Alternatively, the divergent effects of IL-1R1 KO in the two models could depend on differences in cell-specific IL-1R1 signaling, or the timing of IL-1R1 signaling (e.g., beneficial early but detrimental later after injury). Preliminary data show improved cognitive outcome after repetitive CHI in constitutive neuronal IL-1R1 KO, and after CCI in endothelial IL-1R1 KO mice. However, whether IL-1R1 signaling is important initially, or whether persistent IL-1R1 activation in the chronic period of CHI or CCI maintains functional deficits and induces neurodegeneration remains unknown. This proposal leverages mice engineered for precise cellular and temporal control of brain IL-1R1 expression that will allow for rigorous determination of where (what cell type) and when targeting IL-1R1 can be beneficial in CHI vs. CCI. Our central hypothesis is that persistent neuronal IL-1R1 signaling drives cognitive deficits, synaptic dysfunction, and impaired neuronal proteostasis after CHI whereas endothelial IL-1R1 drives these neuronal processes after CCI. To test this hypothesis, we propose two Specific Aims: (1) Define brain cell type(s) that mediate post-injury motor and cognitive deficits via IL-1R1 in the chronic period of CCI and CHI, and (2) Test the contributions of endothelial and neuronal IL-1R1 to synaptic dysregulation and neurodegeneration in the chronic period of CCI and CHI. Project Number: 1R01NS141974-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: MICHAEL WHALEN | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $322,382 | Activity Code: R01 | Study Section: Brain Injury and Neurovascular Pathologies Study Section[BINP] View on NIH RePORTER: https://reporter.nih.gov/project-details/11364692