Inflammatory regulation of neurotrophin signaling in epileptogenesis

癫痫发生中神经营养蛋白信号传导的炎症调节

基本信息

批准号：
10058296
负责人：
Jianxiong Jiang
金额：
$ 33.25万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
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：
2018-08-03 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058296
关键词：
Ablation Acute Address American Amygdaloid structure Animals Antiepileptic Agents Antiepileptogenic BDNF gene Behavioral Biochemical Biological Models Brain Brain-Derived Neurotrophic Factor CREB1 gene Chronic Clinical Research Cognitive deficits Complement Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Dinoprostone Disease Dose EP4 receptor Electroencephalography Elements Epilepsy Epileptogenesis Event FDA approved GTP-Binding Protein alpha Subunits, Gs Gene Structure Genetic Genetic Transcription Glial Fibrillary Acidic Protein Gliosis Goals Hippocampus (Brain)In Vitro Inflammation Inflammatory Injections Interleukin-1 beta Interleukin-6 Isoenzymes Lead Mediating Mediator of activation protein Mental Depression Messenger RNA Microdialysis Modeling Modification Molecular Molecular Target Mus Mutant Strains Mice Nerve Degeneration Neuroblastoma Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Outcome PLC gamma1 Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phosphorylation Phosphotransferases Play Population Prevention Prevention strategy Process Production Recurrence Regulation Resistance Role Sampling Seizures Severities Signal Pathway Signal Transduction Stains Status Epilepticus TNF gene Testing Time Tropomyosin Variant WFDC2 gene Work acquired epilepsy addiction anxiety-like behavior brain abnormalities comorbidity cytokine design disorder prevention experience experimental study fluoro jade in vivo in vivo Model inhibitor/antagonist interest kainate mouse PGE synthase 1 nervous system disorder neuroinflammation neuron loss neuropathology neurotrophic factor novel novel therapeutics object recognition overtreatment painful neuropathy preclinical study prevent preventable epilepsy promoter receptor response small molecule inhibitor tool transcription factor

项目摘要

PROJECT SUMMARY Epilepsy is a common neurological disorder that afflicts about 1% of the population. Although seizures can be partially controlled by current medications, there is no US FDA-approved drug that can provide disease prevention or modification despite remarkable advances in epilepsy treatment over the past decades. A major obstacle to finding such an antiepileptogenic drug is that the molecular mechanisms by which a normal brain is transformed to generate epileptic seizures remain unsolved. Accumulating evidence from recent clinical and preclinical studies suggests that the abnormal activation of the brain-derived neurotrophic factor (BDNF) receptor TrkB (tropomyosin-related kinase receptor B) and its downstream effector phospholipase Cγ1 (PLCγ1) is sufficient to produce epilepsy following status epilepticus (SE). As TrkB and PLCγ1 are emerging as attractive molecular targets to prevent acquired epilepsy, a key unsolved puzzle is the signaling events that are triggered by SE and cause the irregular BDNF/TrkA activity in the hippocampus, thereby leading to epileptogenesis. In preliminary studies we have demonstrated that the seizure-induced hippocampal BDNF/TrkB abnormality is largely suppressed by blocking prostaglandin E2 (PGE2) synthesis or signaling. Our main hypothesis is that PGE2 via a Gαs-dependent signaling pathway upregulates hippocampal BDNF/TrkB activity and contributes to epileptogenesis following prolonged seizures. Our general approach is to use biochemical, pharmacological, genetic tools, and multiple in vitro and in vivo model systems to test a hypothesis that PGE2 is involved in the hippocampal BDNF induction and TrkB activation after SE, to determine whether seizure-mediated BDNF/TrkB activity involves cAMP/PKA signaling and which Gαs-coupled PGE2 receptor is engaged, and to determine whether PGE2 signaling via its Gαs-coupled receptors plays a dominant role in the development of epilepsy and/or the associated behavioral comorbidities after SE. Successful completion of this project might lead to the discovery of novel molecular targets for the prevention strategies of acquired epilepsy.

项目概要癫痫是一种常见的神经系统疾病，约 1% 的人口患有癫痫症。目前的药物可以部分控制，没有美国 FDA 批准的药物可以提供疾病尽管过去几十年癫痫治疗取得了显着进展，但仍无法预防或改变。寻找这种抗癫痫药物的障碍是正常大脑的分子机制转化产生癫痫发作的问题仍未得到解决。临床前研究表明脑源性神经营养因子（BDNF）的异常激活受体 TrkB（原肌球蛋白相关激酶受体 B）及其下游效应磷脂酶 Cγ1 (PLCγ1) 随着 TrkB 和 PLCγ1 的出现，足以在癫痫持续状态 (SE) 后产生癫痫。预防获得性癫痫的有吸引力的分子靶标，一个未解决的关键难题是信号事件由 SE 触发并引起海马 BDNF/TrkA 活性不规则，从而导致在初步研究中，我们已经证明癫痫发作诱发的海马。 BDNF/TrkB 异常在很大程度上是通过阻断前列腺素 E2 (PGE2) 合成或信号传导来抑制的。主要假设是 PGE2 通过 Gαs 依赖性信号通路上调海马 BDNF/TrkB 活动并导致长期癫痫发作后的癫痫发生。我们的一般方法是使用。生物化学、药理学、遗传工具以及多个体外和体内模型系统来测试假设 PGE2 参与 SE 后海马 BDNF 诱导和 TrkB 激活，确定癫痫介导的 BDNF/TrkB 活性是否涉及 cAMP/PKA 信号传导以及哪些 Gαs 偶联 PGE2 受体参与，并确定 PGE2 信号传导是否通过其 Gαs 偶联受体发挥作用 SE 后癫痫和/或相关行为合并症的发展中起主导作用。该项目的成功完成可能会发现新的预防分子靶点获得性癫痫的治疗策略。