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-canonical NF-kappaB signaling in TBI and its role in Sur1-Trpm4 expression, is expected to identify novel, drugable targets to address post-TBI cognitive dysfunction, anxiety, and depression.

Public Health Relevance

Traumatic brain injury (TBI) is the leading cause of long-term disability in children and young adults. In the US, an estimated 1.7 million people sustain a TBI annually, and about 5.3 million people live with a disability related to TBI. The estimated cost of TBI in 2000 was $406 billion. Mood disturbances, especially depressive disorders, are among the most frequent neuropsychiatric complications of TBI. Depression is diagnosed in 10? 77% of patients with TBI. Major depression hinders a patient's recovery, and is associated with executive dysfunction, negative affect, and prominent anxiety symptoms. TBI also affects cognition, including attention, processing speed and working memory, with a prevalence of 40?60% in patients 1?3 months after TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS102589-04
Application #
9923772
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bellgowan, Patrick S F
Project Start
2017-07-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
King, Zachary A; Sheth, Kevin N; Kimberly, W Taylor et al. (2018) Profile of intravenous glyburide for the prevention of cerebral edema following large hemispheric infarction: evidence to date. Drug Des Devel Ther 12:2539-2552
Stokum, Jesse A; Kwon, Min S; Woo, Seung K et al. (2018) SUR1-TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling. Glia 66:108-125