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：
10303038
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/10303038
关键词：
Ablation Acute Address American Amygdaloid structure Animal Experiments 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 Darkness 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 In Vitro Inflammation Inflammatory Injections Interleukin-1 beta Interleukin-6 Isoenzymes Light Mediating Mediator 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 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 antagonist anxiety-like behavior brain abnormalities comorbidity cytokine design disorder prevention experience experimental study fluoro jade in vivo in vivo Model inhibitor interest kainate mouse PGE synthase 1 nervous system disorder neuroinflammation neuron loss neuropathology neurotrophic factor novel novel therapeutics object recognition painful neuropathy pharmacologic 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.

项目摘要癫痫是一种常见的神经系统疾病，影响约1％的人群。虽然癫痫发作可能是由当前药物部分控制，没有美国FDA批准的药物可以提供疾病在过去的几十年中，预防或修改目的地在癫痫治疗方面取得了显着进步。专业找到这种抗癫痫药的障碍是正常大脑的分子机制转化以产生癫痫发作尚未解决。从最近的临床和临床前研究表明，脑衍生的神经营养因子（BDNF）的异常激活受体TRKB（Tropomyosin相关激酶受体B）及其下游效应子磷脂酶Cγ1（PLCγ1）足以产生癫痫持续状态（SE）。随着TRKB和PLCγ1的出现有吸引力的分子靶标可预防获得癫痫的癫痫，一个关键的未解决难题是信号事件由SE触发，并在海马中引起不规则的BDNF/TRKA活性，从而导致癫痫发生。在初步研究中，我们证明了癫痫发作诱导的海马 BDNF/TRKB绝对性在很大程度上通过阻断前列腺素E2（PGE2）合成或信号传导抑制。我们的主要假设是通过GαS依赖性信号通路PGE2上调了海马BDNF/TRKB 长期癫痫发作后的活性并有助于癫痫发生。我们的一般方法是使用生化，药物，遗传工具以及多个体外和体内模型系统测试假设PGE2参与SE后海马BDNF诱导和TRKB激活，确定癫痫发作介导的BDNF/TRKB活性是否涉及CAMP/PKA信号和GαS耦合 PGE2受体参与，并确定PGE2信号是否通过其GαS耦合受体发挥作用 SE之后的癫痫发育和/或相关的行为合并症的主要作用。成功完成该项目可能会导致发现预防的新分子靶标获得癫痫的策略。