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

• 批准号: 8003009
• 负责人: Rebecca Benham Vautour
• 金额: $ 3.42万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 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/8003009
• 关键词: 3-aminobutyric acid; Affect; Animal Model; Brain-Derived Neurotrophic Factor; Co-Immunoprecipitations; Complex; Cyclic AMP; Disease; Down-Regulation; Epilepsy; Epileptogenesis; Exhibits; Foundations; Future; GABA-A Receptor; Gene Silencing; Health; Human; Injury; Intractable Epilepsy; Janus kinase; Laboratories; Mediating; Memory; Mental Depression; Modeling; Molecular; NGFR Protein; Nerve Growth Factor Receptors; Neurons; Neurotransmitter Receptor; Neurotransmitters; Pathway interactions; Patients; Pilocarpine; Play; Predisposition; Process; Recurrence; Risk; Role; STAT protein; Seizures; Signal Pathway; Signal Transduction; Status Epilepticus; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Transcriptional Activation; Unconscious State; Up-Regulation; chromatin immunoprecipitation; effective therapy; experience; gamma-Aminobutyric Acid; in vivo; member; nervous system disorder; new therapeutic target; novel; protein protein interaction; public health relevance; receptor downregulation

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Epilepsy is a neurological disorder affecting more than 50 million people worldwide (Epilepsy Foundation, 2008). Alterations in neurotransmitter receptor subunits may contribute to seizure susceptibility in one form of epilepsy, temporal lobe epilepsy. The proposed studies will examine the signaling pathway contributing to these changes with the hope of identifying novel targets for more effective treatment of epilepsy.

描述（由申请人提供）： 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5000多万人。颞叶癫痫（TLE）是癫痫的一种常见形式，其中癫痫发作源自颞叶。TLE可以使人衰弱，因为许多患者经历记忆功能受损和抑郁，或由于意识丧失而遭受与癫痫相关的损伤。此外，每年有多达50 000人死于癫痫发作和相关原因。由于这种严重的健康风险的可能性，重要的是要了解TLE背后的分子机制，以更好地治疗这种疾病。癫痫神经元在癫痫发作期间表现出不同的活动，由包括3-氨基丁酸（GABA）在内的神经递质控制。A型GABA受体组成的改变可能有助于癫痫发作的易感性。特别是，在人类和TLE动物模型中，在长时间癫痫发作后观察到14个亚基的上调和11个亚基的下调。我们的实验室已经鉴定出脑源性神经营养因子（BDNF）是通过激活Janus激酶（JAK）/信号转导子和转录激活子（STAT）途径介导11下调的关键调节因子，该途径控制诱导型cAMP早期阻遏物（ICER）的表达。我们的一般假设是，BDNF信号通过JAK/STAT途径下调11表达癫痫持续状态（SE）后，导致在癫痫发生过程中起关键作用的抑制受损。使用多种技术，包括在培养和体内的基因沉默，染色质免疫沉淀（ChIP），和蛋白质/蛋白质相互作用的免疫共沉淀，JAK/STAT信号通路的特定组件激活的前或成熟形式的BDNF将被确定。我们还将确定是否有神经营养因子受体TrkB和p75 NTR与JAK/STAT复合物的直接关联，以及JAK/STAT激活在毛果芸香碱TLE模型中对癫痫发生的潜在作用。拟议的研究为直接鉴定由SE激活的BDNF诱导的JAK/STAT通路的不同成员奠定了基础，有望为未来治疗难治性癫痫以及显示11亚基表达减少的其他疾病提供新的治疗靶点。 公共卫生相关性： 癫痫是一种神经系统疾病，影响全球超过5000万人（癫痫基金会，2008）。神经递质受体亚单位的改变可能有助于癫痫的一种形式，颞叶癫痫发作的易感性。拟议的研究将检查导致这些变化的信号通路，希望确定更有效治疗癫痫的新靶点。