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：
10170443
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170443
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 therapeutic intervention 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）是神经精神疾病发生的主要危险因素。受伤后很长时间内出现的问题会对生活质量产生负面影响。先前对 TBI 动物模型的研究多次表明，不良神经行为后遗症，包括认知功能障碍、焦虑和抑郁样症状与涉及小胶质细胞的慢性先天免疫反应有关星形胶质细胞。尽管它在涉及大多数器官的多种炎症性疾病中具有重要的记录令人惊讶的是，包括大脑在内的非典型 NF-kappaB 信号传导 (p52:RelB) 尚未被识别之前在 TBI 中。我们实验室的新工作证明了非典型 NF-kappaB 的新发现肿瘤坏死因子样弱凋亡诱导剂 (TWEAK) 的信号传导在 TBI 中很突出，尤其是在 TBI 中星形胶质细胞，并持续数月。新的工作还确定了非典型 NF- 的一个新的下游目标 kappaB——Sur1-Trpm4 通道。 Sur1-Trpm4 以前被认为与血脑屏障功能障碍有关，但与 TBI 后星形胶质细胞功能或 TBI 后神经行为缺陷无关。我们的初步数据显示 TWEAK- 诱导的非典型 NF-κB 信号在 TBI 后 1 个月内逐渐上调，并且可能是负责星形胶质细胞中 Sur1-Trpm 的转录表达。此外，我们的初步数据表明星形胶质细胞Sur1-Trpm4在调节下游表达中起着至关重要的作用趋化因子/离子型效应器、趋化因子（C-C 基序）配体 2 (CCL2)，与炎症和 TBI 后的神经行为缺陷。阐明涉及 TWEAK、Sur1-Trpm4 和 CCL2 的病理三联征星形胶质细胞中的研究将确定非典型 NF-kappaB 在 TBI 中的作用，并将鉴定新的、可药物化的目标是解决 TBI 后神经行为异常问题。越来越深入的理解非经典 NF-kappaB 信号传导有望突出选择性靶向的新治疗策略。描述：在目标 1 中，延迟（第 3 天）给予格列本脲以及星形胶质细胞特异性药物在雄性和雌性的两种 TBI 小鼠模型中删除 Abcc8/Sur1，我们将确认我们的试点数据显示非典型 NF-kappaB 信号传导、Sur1-Trpm4 表达和 CCL2 表达是共同的存在于 TBI 后体内星形胶质细胞中，并且 CCL2 表达和神经行为与星形胶质细胞Sur1。在目标 2 中，我们将证实并扩展来自大脑的体内和体外初步数据输注 TWEAK、染色质免疫沉淀和膜片钳以确定非典型 NF-的作用 kappaB 在功能性 Sur1-Trpm4 通道表达中的作用。在目标 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/离子型效应器，CCL2 通过活化 T 细胞的核因子。这个项目，首先检查 TBI 中的非典型 NF-kappaB 信号传导及其在 Sur1-Trpm4 表达中的作用，预计确定新的、可药物治疗的靶点来解决 TBI 后认知功能障碍、焦虑和抑郁问题。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Kir6.2, the Pore-Forming Subunit of ATP-Sensitive K+ Channels, Is Overexpressed in Human Posttraumatic Brain Contusions.

Kir6.2 是 ATP 敏感 K 通道的成孔亚基，在人类创伤后脑挫伤中过度表达。

DOI：
10.1089/neu.2017.5619
发表时间：
2019-01-01
期刊：
Journal of neurotrauma
影响因子：
4.2
作者：
Lidia Castro;Montoya Noelia;M. Vidal;D. Sánchez;D. Gándara;E. Martínez;M. Cicuéndez;M. Poca;J. Simard;J. Sahuquillo
通讯作者：
J. Sahuquillo

Magnetic Resonance Imaging Pilot Study of Intravenous Glyburide in Traumatic Brain Injury.

静脉注射格列本脲治疗创伤性脑损伤的磁共振成像初步研究。

DOI：
发表时间：
2020-01-01
期刊：
影响因子：
4.2
作者：
Eisenberg, Howard M;Shenton, Martha E;Pasternak, Ofer;Simard, J Marc;Okonkwo, David O;Aldrich, Christina;He, Feng;Jain, Sonia;Hayman, Erik G
通讯作者：
Hayman, Erik G