# Non-canonical NF-kappaB signaling and Sur1-Trpm4 in traumatic brain injury

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $337,969

## Abstract

BACKGROUND: Traumatic brain injury (TBI) is a major risk factor for the development of neuropsychiatric
problems long after injury that negatively impact quality-of-life. Previous work in animal models of TBI has
repeatedly shown that adverse neurobehavioral sequelae, including cognitive dysfunction, anxiety, and
depression-like symptoms are associated with chronic innate immune responses involving microglia and
astrocytes. Despite its documented importance in numerous inflammatory conditions involving most organs
including the brain, surprisingly, non-canonical NF-kappaB signaling (p52:RelB) has not been identified
previously in TBI. New work from our laboratory demonstrates the novel finding that non-canonical NF-kappaB
signaling by tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is prominent in TBI, especially in
astrocytes, and persists for months. New work also identifies a novel downstream target of non-canonical NF-
kappaB -- the Sur1-Trpm4 channel. Sur1-Trpm4 previously was linked to blood-brain barrier dysfunction, but
not to post-TBI astrocyte function or post-TBI neurobehavioral deficits. Our preliminary data show that TWEAK-
induced non-canonical NF-kappaB signaling is upregulated progressively during 1 month post-TBI, and may be
responsible for transcriptional expression of Sur1-Trpm in astrocytes. Moreover, our preliminary data suggest
that astrocytic Sur1-Trpm4 plays a crucial role in regulating the expression of the downstream
chemokine/ionotropic effector, chemokine (C-C motif) ligand 2 (CCL2), implicated in inflammation and
neurobehavioral deficits post-TBI. Elucidating the pathological triad involving TWEAK, Sur1-Trpm4 and CCL2
in astrocytes will establish the role of non-canonical NF-kappaB in TBI, and will identifying novel, drugable
targets to address post-TBI neurobehavioral abnormalities. An increasingly sophisticated understanding of
non-canonical NF-kappaB signaling promises to highlight novel therapeutic strategies for selective targeting.
DESCRIPTION: In Aim 1, using delayed (day-3) administration of glibenclamide along with astrocyte-specific
deletion of Abcc8/Sur1 in two mouse models of TBI in males and females, we will confirm our pilot data
showing that non-canonical NF-kappaB signaling, Sur1-Trpm4 expression and CCL2 expression are co-
present in astrocytes in vivo post-TBI, and that CCL2 expression and neurobehavior are explicitly linked to
astrocytic Sur1. In Aim 2, we will corroborate and expand upon in vivo and in vitro preliminary data from brain
infusion of TWEAK, chromatin immunoprecipitation, and patch clamp to establish the role of non-canonical NF-
kappaB in the expression of functional Sur1-Trpm4 channels. In Aim 3, we will expand upon in vivo and in vitro
preliminary data to establish the role of Sur1-Trpm4 in regulating Ca2+-dependent gene transcription of the
downstream chemokine/ionotropic effector, CCL2 via nuclear factor of activated T cells. This project, the first to
examine non-can...

## Key facts

- **NIH application ID:** 10170443
- **Project number:** 5R01NS102589-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** J. Marc Simard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $337,969
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170443

## Citation

> US National Institutes of Health, RePORTER application 10170443, Non-canonical NF-kappaB signaling and Sur1-Trpm4 in traumatic brain injury (5R01NS102589-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10170443. Licensed CC0.

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