Fn14, non-canonical NF-kappaB and downstream signaling in neuropathic pain

Fn14、非典型 NF-kappaB 和神经性疼痛中的下游信号传导

基本信息

批准号：
10474323
负责人：
J. Marc Simard
金额：
$ 37.31万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474323
关键词：
Animals Antibodies Apoptosis Promoter Astrocytes Brain CXC Chemokines Calcineurin Cells Centers for Disease Control and Prevention (U.S.)Chronic Cytokine Receptors Data Development Etiology Exhibits Exposure to Fibroblast Growth Factor Genes Genetic Genetic Transcription Glial Fibrillary Acidic Protein Glyburide Goals HIV HIV Envelope Protein gp120 In Vitro Inflammation Inflammatory Interleukin-6 Laboratories Lead Ligands Light Methods Modeling Molecular Mus NF-kappa B Nerve Nerve Growth Factors Neuroglia Neurons Opiate Addiction Opioid Organ Pain Research Pain management Pathogenesis Pathologic Pathway interactions Patients Peripheral nerve injury Persons Pharmaceutical Preparations Pharmacology Phenotype Play Prevention Guidelines Proteins Public Health Role Signal Transduction Site TNF gene TNFRSF5 gene Tissues Up-Regulation Work addiction allodynia beta-Chemokines chemokine chemokine receptor chromatin immunoprecipitation chronic pain cytokine dorsal horn evidence based guidelines experimental study in vivo mu opioid receptors neuroinflammation new therapeutic target non-opioid analgesic novel opioid epidemic opioid overdose pain behavior pain model painful neuropathy prescription opioid public health relevance

项目摘要

BACKGROUND: The ongoing opioid epidemic is driven in part by legitimate use of opioids prescribed for neuropathic pain. Targeting alternative pathways for pain control using non-addicting drugs is a major goal of neuropathic pain research. After peripheral nerve injury (PNI), cytokines and chemokines are upregulated centrally, where they contribute mechanistically to the pathogenesis of neuropathic pain. Reactive astrocytes in the dorsal horn exhibit a chronically activated, pro-inflammatory secretory (CAPS) phenotype characterized by secretion of numerous factors, including interleukin-6 (IL-6), chemokine C-C motif ligand 2 (CCL2), chemokine C-X-C motif ligand 1 (CXCL1) and nerve growth factor (NGF). The post-PNI astrocytic CAPS phenotype contributes to both inflammation and neuronal hyperactivation via neuronal chemokine receptors, leading to neuropathic pain. Canonical NF-κB signaling is known to play a crucial role, but surprisingly, despite its documented importance in numerous inflammatory conditions involving most organs including the brain, non- canonical NF-κB signaling via the p52:RelB heterodimer has not been identified previously in PNI. New work from our laboratory demonstrates the novel finding that non-canonical NF-κB signaling by the tumor necrosis factor-like weak inducer of apoptosis (TWEAK) / fibroblast growth factor-inducible 14 (Fn14) axis is prominent after PNI, especially in dorsal horn astrocytes, and may be responsible for transcriptional expression of Sur1- Trpm4 in these cells. Moreover, our preliminary data suggest that glial Sur1-Trpm4 plays a crucial role in regulating the expression of IL-6, CCL2 and CXCL1. Our central hypothesis is that, in dorsal horn astrocytes post-PNI, TWEAK-induced non-canonical NF-κB signaling is an upstream regulator of Sur1-Trpm4 expression, and that Sur1-Trpm4, in turn, regulates the expression of the downstream effectors, IL-6, CCL2 and CXCL1, which promote chronic neuroinflammation, neuronal hyperactivation and neuropathic pain. DESCRIPTION: This project has three mechanistic aims. In Aim 1, genetic (Tweak–/–, Fn14–/–, p100–/–, Abcc8–/–, either global or GFAP-specific or GFAP-&-site-specific) and pharmacological (anti-TWEAK antibody, glibenclamide) experiments will be carried out to determine the role of non-canonical NF-κB and Sur1 in GFAP-expressing glia in sciatic n. vs. dorsal horn in two neuropathic pain models: sciatic n. cuffing and sciatic n. exposure to HIV/gp120 protein. In Aim 2, we will expand upon in vivo and in vitro data from chromatin immunoprecipitation to establish the role of non-canonical NF-κB in the expression of functional Sur1-Trpm4 channels. In Aim 3, we will corroborate and expand upon in vivo and in vitro data to establish the role of Sur1- Trpm4 in regulating Ca2+/calcineurin-dependent transcription of IL-6, CCL2 and CXCL1. This project is the first to study non-canonical NF-κB in dorsal horn vs. sciatic n. glia in neuropathic pain, and will help identify novel druggable targets to ameliorate neuropathic pain using non-addictive drugs.

背景：正在进行的阿片类药物流行部分是由于规定的阿片类药物的合法使用而驱动的神经性疼痛。针对使用非添加药物来控制疼痛的替代途径是一个主要目标神经性疼痛研究。周围神经损伤（PNI）后，细胞因子和趋化因子更新中央，它们在机械上为神经性疼痛的发病机理做出了贡献。反应性星形胶质细胞背角表现出长期激活的，促炎的秘密（CAP）表型，其特征是分泌多种因素，包括白介素6（IL-6），趋化因子C-C基序配体2（CCL2），趋化因子 C-X-C基序配体1（CXCL1）和神经生长因子（NGF）。 PNI后星形胶质帽表型通过神经元趋化因子受体有助于炎症和神经元过度激活，导致神经性疼痛。众所周知，规范的NF-κB信号传导起着至关重要的作用，但令人惊讶的是dospite 在涉及大多数器官在内的许多炎症条件下的重要性，包括大脑，非 - 通过p52：RELB Heterodimer的规范NF-κB信号传导先前尚未在PNI中鉴定。新作品从我们的实验室中展示了一个新发现，即肿瘤坏死的非经典NF-κB信号传导类似因子样细胞凋亡（Tweak） /成纤维细胞生长因子诱导因子14（FN14）轴突出的因子样弱诱导剂是突出的 PNI之后，尤其是在背角星形胶质细胞中，可能负责SUR1-的转录表达这些细胞中的trpm4。此外，我们的初步数据表明，Glial Sur1-Trpm4在调节IL-6，CCL2和CXCL1的表达。我们的中心假设是，在背喇叭星形胶质细胞中 PNI后，TWEAK诱导的非典型NF-κB信号传导是SUR1-TRPM4表达的上游调节剂，然后，该SUR1-TRPM4反过来调节下游效应的表达，IL-6，CCL2和CXCL1，促进慢性神经炎症，神经元多激活和神经性疼痛。描述：该项目具有三个机械目标。在AIM 1中，遗传（调整 - / - ，FN14 - / - ，P100 - / - ，，，，， ABCC8 - / - ，全局或GFAP特异性或GFAP - ＆ - 特定于现场）和药物（抗tweak抗体，将进行glibenclamide）实验以确定非典型的NF-κB和SUR1在坐骨神经系统表达GFAP的神经胶质。在两个神经性疼痛模型中的背角与背角：坐骨神经n。袖口和坐骨神经 n。暴露于HIV/GP120蛋白质。在AIM 2中，我们将从染色质中扩展体内和体外数据免疫沉淀以建立非典型NF-κB在功能性SUR1-TRPM4表达中的作用频道。在AIM 3中，我们将证实并扩展体内和体外数据，以确定SUR1-的作用在调节IL-6，CCL2和CXCL1的CA2+/钙调蛋白依赖性转录中的TRPM4。这个项目是第一个在背角与坐骨神经N中研究非典型的NF-κB。神经性疼痛中的神经胶质，将有助于识别新颖使用非添加性药物来改善神经性疼痛的可药物靶标。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion.

DOI：
10.1089/neu.2018.5986
发表时间：
2019-04-01
期刊：
Journal of neurotrauma
影响因子：
4.2
作者：
Gerzanich V;Stokum JA;Ivanova S;Woo SK;Tsymbalyuk O;Sharma A;Akkentli F;Imran Z;Aarabi B;Sahuquillo J;Simard JM
通讯作者：
Simard JM

The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness.

DOI：
10.1371/journal.pone.0242427
发表时间：
2020
期刊：
PloS one
影响因子：
3.7
作者：
Keledjian K;Tsymbalyuk O;Semick S;Moyer M;Negoita S;Kim K;Ivanova S;Gerzanich V;Simard JM
通讯作者：
Simard JM

Blast-induced brain injury in rats leads to transient vestibulomotor deficits and persistent orofacial pain.