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

创伤性脑损伤中的非典型 NF-kappaB 信号传导和 Sur1-Trpm4

基本信息

批准号：
9362994
负责人：
J. Marc Simard
金额：
$ 33.8万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9362994
关键词：
Acute Address Affect Animal Model Animals Anxiety Apoptosis Promoter Area Astrocytes Attention Behavior Blood - brain barrier anatomy Brain Child Chronic Climacteric Cognition Cytokine Receptors Data Depressive disorder Development Diagnosis Diffuse Drug Targeting Edema Elements Executive Dysfunction Exhibits Female Fibroblast Growth Factor Functional disorder Genes Genetic Transcription Glyburide Hemorrhage Impaired cognition In Vitro Inflammation Inflammatory Infusion procedures Injury Innate Immune Response Knockout Mice Laboratories Ligands Link Major Depressive Disorder Mental Depression Mental Health Microglia Molecular Mus NF-kappa B Organ Pathologic Patients Play Prevalence Quality of life Recovery Reporting Risk Factors Role Short-Term Memory Signal Transduction TBI Patients TNF gene TNFRSF5 gene Time Traumatic Brain Injury Triad Acrylic Resin Up-Regulation Work anxiety symptoms associated symptom chemokine chromatin immunoprecipitation controlled cortical impact cost disability disturbance in affect endothelial dysfunction experimental study fluid percussion injury in vivo male mouse model negative affect neurobehavior neurobehavioral neuroinflammation neuropathology neuropsychiatry new therapeutic target novel novel therapeutics nuclear factors of activated T-cells patch clamp prevent processing speed public health relevance young adult

项目摘要

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-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.

背景：创伤性脑损伤（TBI）是神经精神疾病发展的主要危险因素