Thursday, May 19, 2022
5/19/2022
ABSTRACT Management of neuroinflammation is a promising target for improving patient outcomes following a traumatic brain injury (TBI), and substantial evidence suggests therapies targeting the interleukin-1 receptor (IL-1R1) pathway may control neuroinflammation. Despite the promise, there have been limited attempts to move anti-interleukin-1 (IL-1) drugs forward for TBI neuroprotection. We hold that a critical reason for the lack of progress on this promising target is the incomplete understanding of the mechanistic underpinnings of IL-1 signaling after a TBI. It is well-recognized that the clinical picture of TBI is a spectrum of different primary injury mechanisms and injury severities, and that it is necessary to understand the secondary injury mechanism as they relate to the primary injury. Over 75% of TBIs are classified as mild. While not all TBIs lead to neurodegeneration, a mild TBI can result in progressive brain atrophy and persistent cognitive dysfunction, and is a known risk factor for the development of Alzheimer’s disease and related dementias. The current knowledge of IL-1 / IL-1R1 signaling after a TBI is almost exclusively following a moderate-to-severe injury. Using our novel genetic mouse models that allow for cell-type regulation of IL-1R1 signaling, and our model of mild TBI caused by a closed head injury (CHI) we will address this fundamental gap in our knowledge by testing the role of IL-1R1 following a mild TBI, and for the first time, define a cellular mechanism for the pathological effects of IL-1R1 following a mild TBI. Importantly our exciting preliminary data has uncovered a critical role for the brain endothelium in regulating neuroinflammation, which is dependent on IL-1R1. Our preliminary results have led us to propose the overall hypothesis: Secondary neuronal injury following a mild TBI is driven by neuroinflammation and vascular dysfunction, which can be reduced through suppression of IL-1R1. The actions of IL-1R1 following a mild TBI will require the involvement of endothelial cells. We will test our hypothesis in the following aims: Aim 1: Assess the role of endothelial IL-1R1 signaling in the neuroinflammatory feedforward loop. Aim 2: Define the role of endothelial IL-1R1 signaling in the vascular response to a CHI. Aim 3: Delineate the role of endothelial IL-1R1 signaling on synaptic plasticity and spatial learning and memory following a CHI. Successful completion of these studies will increase our understanding of the role of IL-1R1 after a mild TBI, and define the role of the brain endothelium in the neuroinflammatory response to a mild TBI. Our results will fill a critical knowledge gap concerning how best to target neuroinflammation to achieve neuroprotection after a mild TBI, and potential for other disease associated with neuroinflammation (i.e., Alzheimer’s disease).
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
