Mechanisms of Chronic Blood-Brain Barrier Dysfunction after Traumatic Brain Injury - Damage to the blood-brain barrier (BBB) causes neurodegeneration and occurs early in the pathogenesis of dementia and neurodegenerative diseases. BBB damage in the chronic period of traumatic brain injury (TBI) contributes to progressive neurodegeneration, but how chronic BBB damage is initiated and maintained, and whether it adversely affects cognitive outcomes after TBI, remain unknown. The receptor interacting protein kinase-1 (RIPK1) is a master regulator of cell death, interleukin-1 beta (IL-1B) activation, and NFkB-dependent inflammation. Our preliminary data show that RIPK1,RIPK3, and IL-1 beta are persistently activated in brain endothelium after controlled cortical impact (CCI) in mice and that chronic BBB damage and blood vessel density are markedly reduced in both RIPK1 kinase dead and caspase-1/11 deficient mice, supporting the idea that RIPK1 and inflammasome activation are targetable drivers of chronic BBB damage after CCI. The proposed work will fill an important gap in the cellular and molecular understanding of how TBI perpetuates chronic BBB damage leading to dementia, that may also generalize to millions of people suffering with Alzheimer’s and other neurodegenerative diseases. Our central hypothesis is that RIPK1-RIPK3-IL-1R1 signaling is essential to neovascularization and chronic BBB damage after TBI, and that targeting this pathway to reduce chronic BBB damage after CCI will reduce cognitive deficits and neurodegeneration. To test this hypothesis, we propose three Specific Aims: Aim 1: Identify an endothelial RIPK1-RIPK3-IL-1b pathway that drives post-traumatic angiogenesis, and test whether nascent blood vessels exhibit BBB damage in the chronic period after CCI. Aim 2: Test whether inhibition of a RIPK1-RIPK3-inflammasome pathway in the chronic period after CCI can repair established BBB damage. Aim 3: Define upstream regulatory and downstream effector mechanisms by which IL-1 beta activation drives chronic BBB damage after CCI. Impact: Successful completion of the Aims may have profound implications for novel therapies to prevent progression of TBI and other neurodegenerative diseases by targeting BBB damage in the chronic period, for which no specific therapies currently exist.
