BDNF and JAK/STAT: partners in seizure-induced GABA-A receptor downregulation

BDNF 和 JAK/STAT：癫痫引起的 GABA-A 受体下调的伙伴

基本信息

批准号：
8114125
负责人：
Rebecca Benham Vautour
金额：
$ 3.49万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8114125
关键词：
3-aminobutyric acid Affect Aminobutyric Acids Animal Model Animals Binding Brain Brain-Derived Neurotrophic Factor Co-Immunoprecipitations Complex Coupled Cyclic AMP Cyclic AMP-Responsive DNA-Binding Protein Development Disease Down-Regulation Epilepsy Epileptogenesis Exhibits Foundations Future GABA-A Receptor Gene Expression Regulation Gene Silencing Genes Genetic Transcription Health Human Injury Intractable Epilepsy Janus kinase Laboratories Link Mediating Memory Mental Depression MicroRNAs Modeling Molecular NGFR Protein Nerve Growth Factor Receptors Neuraxis Neurons Neurotransmitter Receptor Neurotransmitters Neurotrophic Tyrosine Kinase Receptor Type 2 Pathway interactions Patients Phosphotransferases Pilocarpine Play Population Predisposition Process Protein Isoforms Proteins Recurrence Regulation Regulatory Element Repression Reproducibility Research Risk Role STAT protein Seizures Signal Pathway Signal Transduction Status Epilepticus Synapses System Techniques Temporal Lobe Temporal Lobe Epilepsy Testing Training Transcriptional Activation Unconscious State Up-Regulation Viral Viral Vector Work chromatin immunoprecipitation dentate gyrus effective therapy experience gamma-Aminobutyric Acid gene repression granule cell in vitro Model in vivo member mind control nervous system disorder neuronal excitability new therapeutic target novel prevent promoter protein protein interaction receptor receptor downregulation research study response

项目摘要

Epilepsy is a neurological disorder characterized by recurrent seizures, affecting more than 50 million people worldwide. Temporal lobe epilepsy (TLE) is a common form of epilepsy, where seizures arise from the temporal lobe. TLE can be debilitating, as many patients experience impaired memory function and depression, or suffer seizure-related injuries due to loss of consciousness. Furthermore, up to 50,000 people die each year from seizures and related causes. With the potential for such serious health risks it is important to understand the molecular mechanisms behind TLE to better treat the disorder. Epileptic neurons exhibit distinct activity during seizures, controlled by neurotransmitters including 3-aminobutyric acid (GABA). Altered type A GABA receptor composition may contribute to seizure susceptibility. In particular, an upregulation of 14 and a downregulation of 11 subunits are observed after prolonged seizures in humans and in TLE animal models. Our laboratory has identified brain derived neurotrophic factor (BDNF) as a key regulator that mediates 11 downregulation through its activation of the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway, that controls expression of inducible cAMP early repressor (ICER). Our general hypothesis is that BDNF signals through the JAK/STAT pathway to downregulate 11 expression after status epilepticus (SE), resulting in impaired inhibition that plays a critical role in the process of epileptogenesis. Using a variety of techniques including gene silencing in culture and in vivo, chromatin immunoprecipitation (ChIP), and co-immunoprecipitation of protein/protein interactions, specific components of the JAK/STAT signaling pathway activated by either the pro- or mature forms of BDNF will be identified. We will also determine whether there is a direct association of neurotrophin receptors TrkB and p75NTR with the JAK/STAT complex, as well as the potential role of JAK/STAT activation to epileptogenesis in the pilocarpine TLE model. The proposed studies lay the foundation for directly identifying distinct members of the BDNF- induced JAK/STAT pathway activated by SE, with the promise of providing novel therapeutic targets for future treatment of intractable epilepsy as well as other disorders that display reduced 11 subunit expression.

癫痫是一种以反复发作为特征的神经系统疾病，影响着全球超过 5000 万人。颞叶癫痫 (TLE) 是一种常见的癫痫形式，癫痫发作源自颞叶。 TLE 可能会使人衰弱，因为许多患者会经历记忆功能受损和抑郁，或因意识丧失而遭受癫痫相关的伤害。此外，每年有多达 50,000 人死于癫痫发作和相关原因。由于存在如此严重的健康风险，了解 TLE 背后的分子机制对于更好地治疗这种疾病非常重要。癫痫神经元在癫痫发作期间表现出独特的活动，由 3-氨基丁酸 (GABA) 等神经递质控制。 A 型 GABA 受体组成的改变可能导致癫痫易感性增加。特别是，在人类和 TLE 动物模型中，长时间癫痫发作后观察到 14 个亚基上调和 11 个亚基下调。我们的实验室已确定脑源性神经营养因子 (BDNF) 是一个关键调节因子，通过激活 Janus 激酶 (JAK)/信号转导器和转录激活因子 (STAT) 途径介导 11 下调，控制诱导型 cAMP 早期阻遏蛋白的表达。冰激凌）。我们的一般假设是，在癫痫持续状态（SE）后，BDNF 通过 JAK/STAT 通路发出信号，下调 11 的表达，导致抑制受损，而抑制在癫痫发生过程中发挥着关键作用。使用多种技术，包括培养物和体内的基因沉默、染色质免疫沉淀 (ChIP) 以及蛋白质/蛋白质相互作用的免疫共沉淀，由 BDNF 的前体或成熟形式激活 JAK/STAT 信号通路的特定成分将被识别。我们还将确定神经营养蛋白受体 TrkB 和 p75NTR 是否与 JAK/STAT 复合物直接相关，以及 JAK/STAT 激活对毛果芸香碱 TLE 模型中癫痫发生的潜在作用。拟议的研究为直接识别 SE 激活的 BDNF 诱导的 JAK/STAT 通路的不同成员奠定了基础，有望为未来治疗顽固性癫痫以及其他 11 亚基表达减少的疾病提供新的治疗靶点。