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：
9923772
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 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923772
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 affective disturbance anxiety symptoms associated symptom chemokine chromatin immunoprecipitation controlled cortical impact cost estimate disability 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）是神经精神病发展的主要危险因素受伤很长时间会对生活质量产生负面影响的问题。 TBI动物模型的先前工作反复表明，不良神经行为后遗症，包括认知功能障碍，焦虑和抑郁症状症状与涉及小胶质细胞和的慢性先天免疫反应有关星形胶质细胞。尽管在涉及大多数器官的众多炎症条件下，它的重要性是包括大脑，令人惊讶的是，尚未鉴定出非典型的NF-kappab信号传导（p52：relb）以前在TBI中。我们实验室的新作品展示了非经典NF-kappab的小说发现肿瘤坏死因子的信号传导类似于细胞凋亡的弱诱导剂（TWEAK）在TBI中很明显，尤其是在星形胶质细胞持续数月。新作品还确定了非经典NF-的新型下游目标 Kappab-SUR1-TRPM4通道。 SUR1-TRPM4先前与血脑屏障功能障碍有关，但不要在TBI星形胶质细胞功能或TBI神经行为后缺陷。我们的初步数据表明调整 - 在TBI后1个月内，诱导的非典型NF-kappab信号逐渐上调，可能是负责星形胶质细胞中SUR1-TRPM的转录表达。而且，我们的初步数据建议星形胶质细胞SUR1-TRPM4在调节下游的表达中起着至关重要的作用趋化因子/离子性效应子趋化因子（C-C基序）配体2（CCL2），与炎症和 TBI后神经行为缺陷。阐明涉及TWEAK，SUR1-TRPM4和CCL2的病理三合会在星形胶质细胞中，将确定非典型的NF-kappab在TBI中的作用，并将识别出可吸毒的新型，针对TBI后神经行为异常的目标。对非典型的NF-kappab信号有望突出选择性靶向的新型治疗策略。描述：在AIM 1中，使用延迟（第3天）给予Glibenclamide以及星形胶质细胞特异性在男性和女性的两种鼠标TBI模型中删除ABCC8/SUR1，我们将确认我们的飞行员数据表明非典型的NF-kappab信号传导，SUR1-TRPM4表达和CCL2表达是共同的在TBI后体内存在于星形胶质细胞中，并且CCL2表达和神经行为明确链接到星形胶质细胞SUR1。在AIM 2中，我们将证实并扩展体内和体外的大脑初步数据输注调整，染色质免疫沉淀和斑块夹以确立非典型NF-的作用 Kappab在功能性SUR1-TRPM4通道的表达中。在AIM 3中，我们将扩展体内和体外初步数据确定SUR1-TRPM4在调节Ca2+依赖性基因转录中的作用下游趋化因子/离子型效应子，通过活化T细胞的核因子CCL2。这个项目，第一个在TBI中检查非典型的NF-kappab信号传导及其在SUR1-TRPM4表达中的作用，预计将有望确定可解决TBI后认知功能障碍，焦虑和抑郁症的新型可药物目标。