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:
  • 金额:
    $ 33.25万
  • 依托单位:
  • 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

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,约占人口的1%。虽然癫痫发作可以 目前的药物部分控制,没有美国FDA批准的药物可以提供疾病 尽管过去几十年来癫痫治疗取得了显著进展,但仍然存在预防或改变的问题。一个主要 找到这种抗癫痫药物的障碍是正常大脑的分子机制, 转化为癫痫发作的问题仍然没有解决。从最近的临床和 临床前研究表明,脑源性神经营养因子(BDNF)的异常激活 受体Trk B(原肌球蛋白相关激酶受体B)及其下游效应物磷脂酶Cγ1(PLCγ1) 足以在癫痫持续状态(SE)后产生癫痫。随着TrkB和PLCγ1的出现, 有吸引力的分子靶点,以防止获得性癫痫,一个关键的未解决的难题是信号事件, 由SE触发并引起海马中不规则的BDNF/TrkA活性,从而导致 癫痫发生在初步的研究中,我们已经证明,脑损伤诱导的海马 BDNF/TrkB异常在很大程度上通过阻断前列腺素E2(PGE 2)合成或信号传导而被抑制。我们 主要假设是PGE 2通过Gα s依赖的信号通路上调海马BDNF/TrkB 活动,并有助于癫痫发生后,长期癫痫发作。我们的一般方法是使用 生物化学、药理学、遗传学工具以及多种体外和体内模型系统,以测试 假设PGE 2参与SE后海马BDNF诱导和TrkB激活, 确定BDNF/TrkB的活性是否与cAMP/PKA信号有关,以及Gα s与哪些蛋白偶联。 PGE 2受体参与,并确定PGE 2信号转导是否通过其Gα s偶联受体发挥作用。 在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导致发现新的分子靶点,用于预防 获得性癫痫的治疗策略

项目成果

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Jianxiong Jiang其他文献

Jianxiong Jiang的其他文献

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{{ truncateString('Jianxiong Jiang', 18)}}的其他基金

EP2 Antagonists for Ischemic Stroke
EP2 拮抗剂治疗缺血性中风
  • 批准号:
    10723017
  • 财政年份:
    2023
  • 资助金额:
    $ 33.25万
  • 项目类别:
Targeting TRPC3 Channels for Epileptic Seizures
针对癫痫发作的 TRPC3 通道
  • 批准号:
    10531252
  • 财政年份:
    2021
  • 资助金额:
    $ 33.25万
  • 项目类别:
Targeting TRPC3 Channels for Epileptic Seizures
针对癫痫发作的 TRPC3 通道
  • 批准号:
    10353604
  • 财政年份:
    2021
  • 资助金额:
    $ 33.25万
  • 项目类别:
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
  • 批准号:
    10303038
  • 财政年份:
    2018
  • 资助金额:
    $ 33.25万
  • 项目类别:
Prostaglandin signaling following seizures
癫痫发作后的前列腺素信号传导
  • 批准号:
    9755011
  • 财政年份:
    2018
  • 资助金额:
    $ 33.25万
  • 项目类别:
Prostaglandin signaling following seizures
癫痫发作后的前列腺素信号传导
  • 批准号:
    9077177
  • 财政年份:
    2015
  • 资助金额:
    $ 33.25万
  • 项目类别:
Prostaglandin signaling following seizures
癫痫发作后的前列腺素信号传导
  • 批准号:
    9281093
  • 财政年份:
    2015
  • 资助金额:
    $ 33.25万
  • 项目类别:
Prostaglandin signaling following seizures
癫痫发作后的前列腺素信号传导
  • 批准号:
    8487015
  • 财政年份:
    2013
  • 资助金额:
    $ 33.25万
  • 项目类别:
Prostaglandin signaling following seizures
癫痫发作后的前列腺素信号传导
  • 批准号:
    8633064
  • 财政年份:
    2013
  • 资助金额:
    $ 33.25万
  • 项目类别:

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