NRSA Fellowship for Bodnar: Understanding the Immune Response After Mild TBI: Do Endothelial Cells Play a Major Role?

Grants and Contracts Details


A large majority traumatic brain injuries (TBI) - over 90% are classified as mild TBI (mTBI). While most individuals 3 recover from mTBI quickly, a significant minority (10-15%) of patients with mTBI experience persistent 4 symptoms. Yet there are no FDA approved treatments for neuroprotection after TBI. Chronic neuroinflammation and vascular disruption following TBI work together to create an environment that is unfavorable for recovery and results in neurodegeneration. In fact, both of these pathologies have been linked to poor outcomes in TBI as well as other CNS diseases including Alzheimer’s disease and stroke. My preliminary results demonstrate 8 that interleukin-1 (IL-1) signaling through interleukin-1 receptor 1 (IL-1R1) may serve as a link between chronic neuroinflammation and vascular pathology and serve as a therapeutic avenue. IL-1, a major pro-inflammatory cytokine, is upregulated following all TBI severities. IL-1 release has been linked with downstream alterations of the vasculature including changes to the neurovascular unit, blood flow alteration, angiogenesis, and increased release of cytokines, chemokines, and growth factors. While not considered classical immune cells, we have found that brain endothelial cells express a high number of IL-1R1 receptors. Further, we have demonstrated that mice lacking IL-1R1 show reduced neuroinflammation following mTBI. We hypothesize that following mTBI, brain endothelial cells, the IL-1R1 acts as a mediator of the neuroimmune and vascular responses. To test this hypothesis, we will use a closed head injury model (CHI) previously characterized by our lab to model mTBI in mice. Further, we will manipulate IL-1R1 in mouse models using an inducible endothelial cell specific IL-1R1 knockout (eKO), a global knockout in which IL-1R1 has been restored only in the endothelial cells (eRestore), and an IL-1R1 reporter mouse in which the protein and mRNA are labeled. In aim 1, we will determine the cellular and temporal expression changes of IL-1R1 in the brain following CHI using the reporter mice. Through this aim, I will be able to determine how TBI alters IL-1R1 across time as well as IL-1R1 association with arteries, veins and capillaries, while also honing my skills at histology stereological techniques. In aim 2, we will delineate endothelial IL-1R1-dependent neuroinflammatory response following CHI in wildtype, eKO, and eRestore mice. Through this aim I will get experience in animal surgeries as well as RNA isolation and Nanostring gene expression analysis. Finally, in aim 3, we will investigate the involvement eIL1R1 in vascular structure and blood flow changes after TBI. To do this we will use vessel painting and speckle contrast diffusion correlated tomography (scDCT). If we are able to support our hypothesis, we will provide groundwork for development of IL-1 therapeutics for treatment of mTBI, as well as describe a physiological response of the CNS that can be applied to other diseases states. Overall, the question outlined in this proposal not only projects the field forward but also gives significant scientific training which will position me as a strong candidate for post-doctoral work and a future career as an independent scientist.
Effective start/end date9/1/208/31/22


  • National Institute of Neurological Disorders & Stroke: $46,036.00


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