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

基本信息

  • 批准号:
    9976832
  • 负责人:
  • 金额:
    $ 60.88万
  • 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 2025-03-31
  • 项目状态:
    未结题

项目摘要

Blood-brain barrier dysfunction is recognized as both a cause and consequence of seizures in epilepsy. Two key characteristics of barrier dysfunction in epilepsy include 1) neurovascular inflammation and 2) barrier leakage, both of which have been linked to seizures. In spite of increasing evidence supporting that glutamate causes blood-brain barrier dysfunction, knowledge of the associated underlying mechanisms remain to be fully defined. Moreover, therapeutic options for restoring barrier function are currently not available. Thus, there is an unmet critical need to determine how glutamate promotes blood-brain barrier inflammation and leakage and to develop targeted strategies to restore barrier function. The consequence of this unmet need is that development of novel treatments to improve seizure control in epilepsy will likely remain a clinical challenge. The long-term goal of the investigator is to contribute toward the development of mechanism-based strategies to repair blood-brain barrier dysfunction in brain diseases. The overall objective in this application is to establish the efficacy of a mechanism- based intervention to treat blood-brain barrier dysfunction in epilepsy, thereby vertically extending what has been learned under current funding. Based on preliminary data the central hypothesis of this project is that glutamate signaling mediates blood-brain barrier dysfunction and that therapeutic intervention targeting this mechanism will resolve seizure-induced neurovascular inflammation, repair barrier leakage, and reduce seizure burden. The rationale for the proposed research is that its successful completion will provide a robust framework for the continued development and clinical translation of a novel evidence-based therapeutic intervention to help treat seizures in patients with epilepsy. The hypothesis will be tested by pursuing three specific aims: 1) Identify signaling steps responsible for seizure-induced inflammation of the blood-brain barrier. 2) Determine the mechanism responsible for capillary leakage at the human blood-brain barrier, and 3) Develop a therapeutic intervention to reduce seizure burden in a chronic epilepsy model. Under Aim 1, signaling steps that lead to seizure-mediated neuroinflammation will be determined in capillaries isolated from knockout mouse models and verified in vivo. Under Aim 2, key signaling steps that trigger barrier leakage will be determined in human brain capillaries from seizure-free control individuals and from patients with epilepsy. Under Aim 3, an intervention therapy designed to repair barrier dysfunction will be developed and the therapeutic benefit of this strategy on reducing seizure burden will be evaluated in a rat chronic epilepsy model. The proposed research is innovative, because it represents a substantive departure from the status quo by shifting the focus to molecular targets at the blood-brain barrier to resolve neurovascular inflammation, restore barrier function, and improve epilepsy symptoms. The proposed research is significant because it holds the promise of a novel therapeutic approach to repair barrier dysfunction that has translational potential for clinical use to advance treatment of patients with epilepsy and other seizure disorders with underlying barrier dysfunction.
血脑屏障功能障碍被认为是癫痫发作的原因和后果。两个关键

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:
    $ 60.88万
  • 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:
    $ 60.88万
  • 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:
    $ 60.88万
  • 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:
    $ 60.88万
  • 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:
    $ 60.88万
  • 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:
    $ 60.88万
  • 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:
    $ 60.88万
  • 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:
    8687756
  • 财政年份:
    2012
  • 资助金额:
    $ 60.88万
  • 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:
    8887163
  • 财政年份:
    2012
  • 资助金额:
    $ 60.88万
  • 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:
    9107249
  • 财政年份:
    2012
  • 资助金额:
    $ 60.88万
  • 项目类别:

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父母决定的口服孟鲁司特治疗学龄前喘息,并根据花生四烯酸 5 脂氧合酶分层
  • 批准号:
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