# Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $333,480

## Abstract

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).

## Key facts

- **NIH application ID:** 9837501
- **Project number:** 5R01NS103785-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** ADAM D BACHSTETTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $333,480
- **Award type:** 5
- **Project period:** 2018-12-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837501

## Citation

> US National Institutes of Health, RePORTER application 9837501, Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury (5R01NS103785-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9837501. Licensed CC0.

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