Blood-brain barrier function in epilepsy: new targets for therapy

癫痫中的血脑屏障功能:治疗的新目标

基本信息

  • 批准号:
    8687756
  • 负责人:
  • 金额:
    $ 32.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-30 至 2017-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): There is a lack in understanding the mechanism responsible for blood-brain barrier dysfunction in epilepsy. This is a significant clinical challene since it prevents development of a therapy to overcome antiepileptic drug (AED) resistance and reduce seizure burden. Our long-term goal is to elucidate the mechanisms that regulate blood-brain barrier function, which may lead to new strategies to treat epilepsy and other neuro- logical diseases. The objectives in this application are to identify the mechanism(s) by which seizures trig- ger barrier dysfunction, and map key signaling proteins that can potentially serve as targets to repair the blood-brain barrier in epilepsy. Accomplishing these objectives is expected to increase AED brain uptake and reduce seizure burden. Our central hypothesis is that 1) glutamate activates the two-arm LOX/COX pathway, thereby decreasing expression and activity of influx transporters, and upregulating expression and activity of efflux transporters through the COX arm, that 2) glutamate triggers development of barrier leakage through the LOX arm; and that 3) inhibiting cPLA2 to block both arms of the LOX/COX pathway reverses barrier dysfunction and thereby reduces seizure burden. The rationale for this research is that identifying the mechanism(s) responsible for changes in transporter expression and activity, and barrier leakage will potentially provide new targets to improve epilepsy treatment and better control seizures. To accomplish the objectives of this application, our hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism of seizure-induced changes of transporter expression and activity; 2) Deter- mine the mechanism of seizure-induced blood-brain barrier leakage; and 3) Develop a therapeutic strategy to reduce seizures in chronic epileptic rats. In Aim 1, we will block cPLA2 and COX-2 to reverse seizure-induced changes in transporter expression and activity. We will monitor influx and efflux transporter expression and activity, and determine AED brain uptake. In Aim 2, we will inhibit cPLA2 and 5-LOX to map the signaling pathway causing seizure-induced barrier leakage. We will determine expression of tight junction proteins and matrix metalloproteases, and assess barrier leakage. In Aim 3, we will evaluate the therapeutic benefit of cPLA2 inhibition on seizure burden in a rat chronic epilepsy model by determining influx and efflux transporter expression and activity, assessing barrier leakage, and monitoring seizure frequency, duration and severity. The proposed research is innovative because it is focused on a new, integrated strategy that considers blood-brain barrier transporters, as well as barrier leakage, and it is designed specifically to repair te barrier to overcome AED resistance and reduce seizures. The proposed research is significant because the expected outcomes will potentially provide a new strategy to improve pharmacotherapy in patients with resistant epilepsy. The proposed research is translational because cPLA2 inhibitors are under development, and our strategy has potential to be translated into the clinic.
描述(由申请人提供):对癫痫血脑屏障功能障碍的机制缺乏了解。这是一个重大的临床挑战,因为它阻碍了克服抗癫痫药物(AED)耐药性和减轻癫痫发作负担的疗法的开发。我们的长期目标是阐明调节血脑屏障功能的机制,这可能会带来治疗癫痫和其他神经系统疾病的新策略。本申请的目的是确定癫痫发作触发屏障功能障碍的机制,并绘制可能作为修复癫痫血脑屏障靶标的关键信号蛋白。实现这些目标预计将增加 AED 大脑的吸收并减少癫痫发作负担。我们的中心假设是 1) 谷氨酸激活双臂 LOX/COX 途径,从而降低流入转运蛋白的表达和活性,并通过 COX 臂上调流出转运蛋白的表达和活性,2) 谷氨酸通过LOX臂; 3) 抑制 cPLA2 以阻断 LOX/COX 通路的双臂可逆转屏障功能障碍,从而减轻癫痫发作负担。这项研究的基本原理是,确定转运蛋白表达和活性变化以及屏障渗漏的机制可能会为改善癫痫治疗和更好地控制癫痫发作提供新的目标。为了实现本申请的目标,我们的假设将通过追求三个具体目标来检验:1)确定癫痫发作引起的转运蛋白表达和活性变化的机制; 2)确定癫痫引起的血脑屏障渗漏的机制; 3) 制定减少慢性癫痫大鼠癫痫发作的治疗策略。在目标 1 中,我们将阻断 cPLA2 和 COX-2,以逆转癫痫引起的转运蛋白表达和活性的变化。我们将监测流入和流出转运蛋白的表达和活性,并确定 AED 大脑的摄取。在目标 2 中,我们将抑制 cPLA2 和 5-LOX,以绘制导致癫痫引起的屏障渗漏的信号通路。我们将确定紧密连接蛋白和基质金属蛋白酶的表达,并评估屏障渗漏。在目标 3 中,我们将通过确定流入和流出转运蛋白的表达和活性、评估屏障渗漏以及监测癫痫发作频率、持续时间和严重程度,评估 cPLA2 抑制对大鼠慢性癫痫模型中癫痫发作负担的治疗益处。拟议的研究具有创新性,因为它专注于一种新的综合策略,考虑了血脑屏障转运蛋白以及屏障渗漏,并且专门设计用于修复屏障以克服 AED 耐药性并减少癫痫发作。拟议的研究意义重大,因为预期结果可能会提供一种新的策略来改善难治性癫痫患者的药物治疗。拟议的研究是转化性的,因为 cPLA2 抑制剂正在开发中,我们的策略有潜力转化为临床。

项目成果

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Bjoern Bauer其他文献

Bjoern Bauer的其他文献

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{{ truncateString('Bjoern Bauer', 18)}}的其他基金

Mechanism and Therapeutic Potential of CBD to Repair Blood-Brain Barrier Dysfunction in Epilepsy
CBD修复癫痫血脑屏障功能障碍的机制和治疗潜力
  • 批准号:
    10644405
  • 财政年份:
    2023
  • 资助金额:
    $ 32.34万
  • 项目类别:
Blood-Brain Barrier Repair in Alzheimer’s Disease with Epilepsy
阿尔茨海默病伴癫痫的血脑屏障修复
  • 批准号:
    10613906
  • 财政年份:
    2022
  • 资助金额:
    $ 32.34万
  • 项目类别:
Blood-Brain Barrier Repair in Alzheimer’s Disease with Epilepsy
阿尔茨海默病伴癫痫的血脑屏障修复
  • 批准号:
    10345905
  • 财政年份:
    2022
  • 资助金额:
    $ 32.34万
  • 项目类别:
A novel strategy to overcome the P-gp/BCRP drug efflux system at the blood-brain barrier to improve brain uptake of CNS therapeutics
克服血脑屏障处的 P-gp/BCRP 药物流出系统以改善中枢神经系统治疗药物的大脑摄取的新策略
  • 批准号:
    10452766
  • 财政年份:
    2018
  • 资助金额:
    $ 32.34万
  • 项目类别:
A novel strategy to overcome the P-gp/BCRP drug efflux system at the blood-brain barrier to improve brain uptake of CNS therapeutics
克服血脑屏障处的 P-gp/BCRP 药物流出系统以改善中枢神经系统治疗药物的大脑摄取的新策略
  • 批准号:
    9761586
  • 财政年份:
    2018
  • 资助金额:
    $ 32.34万
  • 项目类别:
A novel strategy to overcome the P-gp/BCRP drug efflux system at the blood-brain barrier to improve brain uptake of CNS therapeutics
克服血脑屏障处的 P-gp/BCRP 药物流出系统以改善中枢神经系统治疗药物的大脑摄取的新策略
  • 批准号:
    10225435
  • 财政年份:
    2018
  • 资助金额:
    $ 32.34万
  • 项目类别:
Blood-brain barrier function in epilepsy: new targets for therapy
癫痫中的血脑屏障功能:治疗的新目标
  • 批准号:
    8458213
  • 财政年份:
    2012
  • 资助金额:
    $ 32.34万
  • 项目类别:
Novel Therapeutic Strategies to Resolve Neurovascular Inflammation and Repair Blood-Brain Barrier Dysfunction in Epilepsy
解决癫痫神经血管炎症和修复血脑屏障功能障碍的新治疗策略
  • 批准号:
    10191056
  • 财政年份:
    2012
  • 资助金额:
    $ 32.34万
  • 项目类别:
Novel Therapeutic Strategies to Resolve Neurovascular Inflammation and Repair Blood-Brain Barrier Dysfunction in Epilepsy
解决癫痫神经血管炎症和修复血脑屏障功能障碍的新治疗策略
  • 批准号:
    9976832
  • 财政年份:
    2012
  • 资助金额:
    $ 32.34万
  • 项目类别:
Novel Therapeutic Strategies to Resolve Neurovascular Inflammation and Repair Blood-Brain Barrier Dysfunction in Epilepsy
解决癫痫神经血管炎症和修复血脑屏障功能障碍的新治疗策略
  • 批准号:
    10380864
  • 财政年份:
    2012
  • 资助金额:
    $ 32.34万
  • 项目类别:

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